Cristina Queralt, Cristina Moreta-Moraleda, Marta Costa, Ferran Grau-Leal, Jeannine Diesch, Carla Vendrell-Ayats, Eva Musulén, Roni H G Wright, Cristina Bugés, José Luis Manzano, Sara Cabrero-de las Heras, Johannes Zuber, Marcus Buschbeck, Sonia-V Forcales, Eva Martínez-Balibrea
<div> <section> <h3> Background</h3> <p>Colorectal cancer (CRC) remains a major global health concern, partly due to resistance to therapy and the lack of new effective treatments for advanced disease. The combination of 5-Fluorouracil (5FU, a thymidylate synthase inhibitor) and irinotecan (a topoisomerase 1 inhibitor) is widely used in first-line and subsequent treatments. This study aimed to identify novel therapeutic targets to enhance combinatorial therapy, improving treatment efficacy and durability of response.</p> </section> <section> <h3> Methods</h3> <p>We performed a loss-of-function screen using HT29 CRC cell line and a retroviral library containing 7296 shRNAs targeting 912 chromatin genes. Cells were then treated with 5FU and SN38 (the active metabolite of irinotecan) or left untreated for 4 weeks. Genes enriched in resistant clones were identified through next-generation sequencing. Amongst candidate genes, PARG was selected for functional validation.</p> </section> <section> <h3> Results</h3> <p>CRISPR/Cas9-mediated knockout (HT29 PARG-KO) resulted in increased global poly(ADP-ribosyl)ation after 5FU and SN38 treatment. PARG depletion led to reduced cell viability and increased apoptosis, particularly after 5FU exposure. Pharmacological PARG inhibition (PDD00017273) synergised with 5FU and SN38 across three CRC models (HT29, DLD1, HT115). In vivo, HT29 PARG-KO xenografts were more sensitive to 5FU. Immunohistochemical analysis of 170 CRC patient tumours revealed that positive PARG expression correlated with poor response to 5FU + Irinotecan, increased liver metastases, and worse long-term survival.</p> </section> <section> <h3> Conclusions</h3> <p>Our findings highlight PARG as a promising therapeutic target for CRC, where its inhibition enhances the efficacy of standard chemotherapy.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li>LOF screening identified PARG as a modulator of CRC response to FUIRI treatment.</li> <li>HT29 PARG-KO cells showed increased PAR, DNA damage, apoptosis, and 5FU sensitivity.</li> <li>Pharmacological PARG inhibition synergised with 5FU and SN38 in CRC cell lines.</li> <li>HT29 PARG-KO tumours exhibited increased sensitivity to 5FU treatment in vivo.</li> <li>PARG e
{"title":"Loss-of-function genetic screen unveils synergistic efficacy of PARG inhibition with combined 5-fluorouracil and irinotecan treatment in colorectal cancer","authors":"Cristina Queralt, Cristina Moreta-Moraleda, Marta Costa, Ferran Grau-Leal, Jeannine Diesch, Carla Vendrell-Ayats, Eva Musulén, Roni H G Wright, Cristina Bugés, José Luis Manzano, Sara Cabrero-de las Heras, Johannes Zuber, Marcus Buschbeck, Sonia-V Forcales, Eva Martínez-Balibrea","doi":"10.1002/ctm2.70543","DOIUrl":"10.1002/ctm2.70543","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Colorectal cancer (CRC) remains a major global health concern, partly due to resistance to therapy and the lack of new effective treatments for advanced disease. The combination of 5-Fluorouracil (5FU, a thymidylate synthase inhibitor) and irinotecan (a topoisomerase 1 inhibitor) is widely used in first-line and subsequent treatments. This study aimed to identify novel therapeutic targets to enhance combinatorial therapy, improving treatment efficacy and durability of response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a loss-of-function screen using HT29 CRC cell line and a retroviral library containing 7296 shRNAs targeting 912 chromatin genes. Cells were then treated with 5FU and SN38 (the active metabolite of irinotecan) or left untreated for 4 weeks. Genes enriched in resistant clones were identified through next-generation sequencing. Amongst candidate genes, PARG was selected for functional validation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>CRISPR/Cas9-mediated knockout (HT29 PARG-KO) resulted in increased global poly(ADP-ribosyl)ation after 5FU and SN38 treatment. PARG depletion led to reduced cell viability and increased apoptosis, particularly after 5FU exposure. Pharmacological PARG inhibition (PDD00017273) synergised with 5FU and SN38 across three CRC models (HT29, DLD1, HT115). In vivo, HT29 PARG-KO xenografts were more sensitive to 5FU. Immunohistochemical analysis of 170 CRC patient tumours revealed that positive PARG expression correlated with poor response to 5FU + Irinotecan, increased liver metastases, and worse long-term survival.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings highlight PARG as a promising therapeutic target for CRC, where its inhibition enhances the efficacy of standard chemotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>LOF screening identified PARG as a modulator of CRC response to FUIRI treatment.</li>\u0000 \u0000 <li>HT29 PARG-KO cells showed increased PAR, DNA damage, apoptosis, and 5FU sensitivity.</li>\u0000 \u0000 <li>Pharmacological PARG inhibition synergised with 5FU and SN38 in CRC cell lines.</li>\u0000 \u0000 <li>HT29 PARG-KO tumours exhibited increased sensitivity to 5FU treatment in vivo.</li>\u0000 \u0000 <li>PARG e","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 12","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12741922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145832909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Juan F. Cardona, Hernando Santamaría-García, Agustín Ibáñez
<p>Cardona JF, Santamaría-García H, Ibáñez A. The biological burden of conflict across populations worldwide. <i>Clin Transl Med</i>. 2025;00:e70574. https://doi.org/10.1002/ctm2.70574</p><p>Contemporary societies are increasingly shaped by multilayered forms of interindividual and intergroup conflict that transcend traditional political or military boundaries.<span><sup>1, 2</sup></span> Violence, forced migration, environmental degradation, institutional fragility and widening social and political polarisation interact to generate complex forms of adversity that affect entire populations. These conditions carry profound consequences for mental and brain health, yet their biological impact remains insufficiently integrated into global health and policy agendas. Recent analyses show that even political polarisation itself now functions as a determinant of population health, shaping stress, trust, behaviour and risk perception.<span><sup>3</sup></span> Thus, understanding the biological burden of conflict requires a genuinely transdisciplinary perspective capable of linking neurobiological mechanisms with social determinants, ecological pressures and institutional dynamics.</p><p>Although classical armed conflicts persist, today's adversities extend beyond the battlefield. Many societies face recent escalating political polarisation, intergroup conflict, radicalisation, recurrent violence, institutional erosion, widening inequality and expanding illicit economies, including the resurgence of narcotrafficking and environmentally destructive extractive activities. High-income regions are not exempt; rising polarisation, mass shootings, hate crimes, digital extremism and climate-related displacement in the United States and Europe illustrate how conflict-like dynamics increasingly permeate daily life (Figure 1).</p><p>Globally, conflict-related adversity is intensifying. Countries such as Ukraine, Gaza, Sudan, Myanmar, Venezuela, Colombia and those across the Sahel experience interrelated crises involving displacement, food insecurity, environmental loss, organised violence and institutional collapse. As the United Nations recently stressed, ethnic violence and nationalist aggression continue to drive conflicts that displace millions and generate prolonged humanitarian emergencies.<span><sup>4</sup></span> Despite differences in political structure or geography, these contexts converge through shared mechanisms such as chronic adversity, disrupted community structures, cumulative stress exposure and the erosion of protective social and ecological systems.</p><p>Colombia provides a clear illustration of how contemporary conflicts can reconfigure themselves across time.<span><sup>5-7</sup></span> After the 2016 Peace Agreement, territorial fragmentation, the proliferation of armed groups, the expansion of illegal economies, and widespread narco-deforestation generated new cycles of violence and displacement. More than one million new displacements sinc
{"title":"The biological burden of conflict across populations worldwide","authors":"Juan F. Cardona, Hernando Santamaría-García, Agustín Ibáñez","doi":"10.1002/ctm2.70574","DOIUrl":"10.1002/ctm2.70574","url":null,"abstract":"<p>Cardona JF, Santamaría-García H, Ibáñez A. The biological burden of conflict across populations worldwide. <i>Clin Transl Med</i>. 2025;00:e70574. https://doi.org/10.1002/ctm2.70574</p><p>Contemporary societies are increasingly shaped by multilayered forms of interindividual and intergroup conflict that transcend traditional political or military boundaries.<span><sup>1, 2</sup></span> Violence, forced migration, environmental degradation, institutional fragility and widening social and political polarisation interact to generate complex forms of adversity that affect entire populations. These conditions carry profound consequences for mental and brain health, yet their biological impact remains insufficiently integrated into global health and policy agendas. Recent analyses show that even political polarisation itself now functions as a determinant of population health, shaping stress, trust, behaviour and risk perception.<span><sup>3</sup></span> Thus, understanding the biological burden of conflict requires a genuinely transdisciplinary perspective capable of linking neurobiological mechanisms with social determinants, ecological pressures and institutional dynamics.</p><p>Although classical armed conflicts persist, today's adversities extend beyond the battlefield. Many societies face recent escalating political polarisation, intergroup conflict, radicalisation, recurrent violence, institutional erosion, widening inequality and expanding illicit economies, including the resurgence of narcotrafficking and environmentally destructive extractive activities. High-income regions are not exempt; rising polarisation, mass shootings, hate crimes, digital extremism and climate-related displacement in the United States and Europe illustrate how conflict-like dynamics increasingly permeate daily life (Figure 1).</p><p>Globally, conflict-related adversity is intensifying. Countries such as Ukraine, Gaza, Sudan, Myanmar, Venezuela, Colombia and those across the Sahel experience interrelated crises involving displacement, food insecurity, environmental loss, organised violence and institutional collapse. As the United Nations recently stressed, ethnic violence and nationalist aggression continue to drive conflicts that displace millions and generate prolonged humanitarian emergencies.<span><sup>4</sup></span> Despite differences in political structure or geography, these contexts converge through shared mechanisms such as chronic adversity, disrupted community structures, cumulative stress exposure and the erosion of protective social and ecological systems.</p><p>Colombia provides a clear illustration of how contemporary conflicts can reconfigure themselves across time.<span><sup>5-7</sup></span> After the 2016 Peace Agreement, territorial fragmentation, the proliferation of armed groups, the expansion of illegal economies, and widespread narco-deforestation generated new cycles of violence and displacement. More than one million new displacements sinc","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12743140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Aging trajectories vary widely across individuals, even under comparable biological and environmental pressures, yet most biomedical frameworks prioritize vulnerability over protection. This perspective proposes a shift towards identifying resilient expotype–phenotypes, defined by combinations of exposures and individual adaptive responses that support unexpectedly healthy aging. We propose multimodal aging clocks (focusing on delayed agers) to address resilience and its phenotypic and expotype contributions. Building on recent evidence from global exposome analyses<span><sup>1-4</sup></span>, multimodal aging clocks<span><sup>1, 5-8</sup></span> and neuroecological frameworks<span><sup>2, 9</sup></span>, we argue that resilience offers an essential dimension for precision brain health.</p><p>The exposome<span><sup>1, 10</sup></span> captures the totality of physical, social and sociopolitical exposures across the lifespan, exerting marked influences on biological, systemic and cognitive health. This multidimensional construct provides a foundation for defining expotypes<span><sup>11</sup></span>, the characteristic combinations of exposures that shape individual risk or protection<span><sup>12</sup></span>. Aging clocks (epigenetic clocks, proteomic or multi-omic clocks, brain clocks and biobehavioural clocks) quantify biological aging relative to chronological time, enabling direct assessment of how exposures modulate aging trajectories. These tools reveal that diverse exposures, from pollution and temperature peaks to structural inequalities and political instability, accelerate biological aging,<span><sup>1, 2, 6</sup></span> whereas enriching environments, cognitive stimulation and social cohesion may delay it. Together, they provide a framework for evaluating how cumulative exposures influence aging across datasets, populations and biological systems<span><sup>12, 13</sup></span>. Thus, the exposome and aging clocks may jointly enable a more mechanistic assessments of how protective and adverse exposures shape biological aging across systems.</p><p>Our recent <i>Nature Medicine</i> study illustrates how biobehavioural age gaps (BBAGs) – the discrepancy between predicted age from protective/risk factors and chronological age – capture delayed or accelerated aging across 40 countries<span><sup>1</sup></span>. BBAGs were estimated using a Gradient Boosting Regressor with 10-fold cross-validation to predict age from biobehavioural factors (risk and protective) in >160 000 participants. The age gap was computed as predicted minus chronological age, with negative values indicating delayed and positive values indicating accelerated aging. To correct regression-to-the-mean, gaps were residualized against chronological age using coefficients from the training set and applied to the test set. Delayed BBAGs were linked to favourable exposomes: cleaner air, inclusive migration contexts, structural and gender equality, and democratic stability. Th
{"title":"Expotype–phenotype resilience and multimodal aging clocks","authors":"Hernan Hernandez, Agustin Ibanez","doi":"10.1002/ctm2.70558","DOIUrl":"10.1002/ctm2.70558","url":null,"abstract":"<p>Aging trajectories vary widely across individuals, even under comparable biological and environmental pressures, yet most biomedical frameworks prioritize vulnerability over protection. This perspective proposes a shift towards identifying resilient expotype–phenotypes, defined by combinations of exposures and individual adaptive responses that support unexpectedly healthy aging. We propose multimodal aging clocks (focusing on delayed agers) to address resilience and its phenotypic and expotype contributions. Building on recent evidence from global exposome analyses<span><sup>1-4</sup></span>, multimodal aging clocks<span><sup>1, 5-8</sup></span> and neuroecological frameworks<span><sup>2, 9</sup></span>, we argue that resilience offers an essential dimension for precision brain health.</p><p>The exposome<span><sup>1, 10</sup></span> captures the totality of physical, social and sociopolitical exposures across the lifespan, exerting marked influences on biological, systemic and cognitive health. This multidimensional construct provides a foundation for defining expotypes<span><sup>11</sup></span>, the characteristic combinations of exposures that shape individual risk or protection<span><sup>12</sup></span>. Aging clocks (epigenetic clocks, proteomic or multi-omic clocks, brain clocks and biobehavioural clocks) quantify biological aging relative to chronological time, enabling direct assessment of how exposures modulate aging trajectories. These tools reveal that diverse exposures, from pollution and temperature peaks to structural inequalities and political instability, accelerate biological aging,<span><sup>1, 2, 6</sup></span> whereas enriching environments, cognitive stimulation and social cohesion may delay it. Together, they provide a framework for evaluating how cumulative exposures influence aging across datasets, populations and biological systems<span><sup>12, 13</sup></span>. Thus, the exposome and aging clocks may jointly enable a more mechanistic assessments of how protective and adverse exposures shape biological aging across systems.</p><p>Our recent <i>Nature Medicine</i> study illustrates how biobehavioural age gaps (BBAGs) – the discrepancy between predicted age from protective/risk factors and chronological age – capture delayed or accelerated aging across 40 countries<span><sup>1</sup></span>. BBAGs were estimated using a Gradient Boosting Regressor with 10-fold cross-validation to predict age from biobehavioural factors (risk and protective) in >160 000 participants. The age gap was computed as predicted minus chronological age, with negative values indicating delayed and positive values indicating accelerated aging. To correct regression-to-the-mean, gaps were residualized against chronological age using coefficients from the training set and applied to the test set. Delayed BBAGs were linked to favourable exposomes: cleaner air, inclusive migration contexts, structural and gender equality, and democratic stability. Th","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12743139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zijian Liu, Jingsheng Yuan, Shitong Su, Jiaqi Han, Ni Zeng, Yuhan Ma, Nianyong Chen, Tao Lv
<div> <section> <h3> Background</h3> <p>Lenvatinib resistance (LR) represents a significant obstacle in hepatocellular carcinoma (HCC) treatment. Aldo-keto reductase family 1 member B10 (AKR1B10) is involved in tumour metabolic reprogramming; however, its role in LR remains unclear.</p> </section> <section> <h3> Methods</h3> <p>Bioinformatics analyses of public databases were integrated and validated in established LR HCC cell lines. Functional assays (CCK-8, flow cytometry and Seahorse XF analysis) were performed to assess proliferation, apoptosis and aerobic glycolysis. Post-translational modifications of AKR1B10 were characterized using co-immunoprecipitation, mass spectrometry and western blot.</p> </section> <section> <h3> Results</h3> <p>AKR1B10 was identified as a critical driver of resistance by establishing a metabolic positive feedback loop. Bioinformatics analyses and experimental validation demonstrated that AKR1B10 upregulation correlates with therapeutic resistance. Functional studies indicated that AKR1B10 promotes resistance by enhancing aerobic glycolysis. Mechanistically, alanyl-tRNA synthetase 1 mediates lactylation modification at AKR1B10 lysine 173 (K173), stabilizing AKR1B10 by blocking ubiquitin (Ub)-proteasomal degradation. Stabilized AKR1B10 interacts physically with lactate dehydrogenase A (LDHA), promoting LDHA phosphorylation at Y10 and accelerating glycolytic lactate production. The increased lactate subsequently induces histone H3K18 lactylation (H3K18la), which transcriptionally upregulates LDHA expression. Thus, a self-reinforcing AKR1B10–lactate–LDHA amplification circuit is formed. Clinical analyses confirmed elevated AKR1B10 expression in LR HCC patient tissues. Importantly, targeting this axis with the AKR1B10 inhibitor epalrestat (EPA) synergized with lenvatinib, overcoming resistance in xenograft mouse models and patient-derived xenograft models.</p> </section> <section> <h3> Conclusions</h3> <p>These findings establish AKR1B10 as both a biomarker and a therapeutic target in HCC. They reveal a novel lactylation-driven glycolytic adaptation mechanism and support the clinical translation of combined EPA–lenvatinib therapy.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li>AKR1B10 confers lenvatinib resistance by enhancing aerobic glycolysis in HCC cells.</li> <li>AKR1B10 undergoes AARS1-mediated lact
{"title":"AARS1-mediated AKR1B10 lactylation stabilizes an aerobic glycolysis-positive feedback loop to drive lenvatinib resistance in hepatocellular carcinoma","authors":"Zijian Liu, Jingsheng Yuan, Shitong Su, Jiaqi Han, Ni Zeng, Yuhan Ma, Nianyong Chen, Tao Lv","doi":"10.1002/ctm2.70561","DOIUrl":"10.1002/ctm2.70561","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Lenvatinib resistance (LR) represents a significant obstacle in hepatocellular carcinoma (HCC) treatment. Aldo-keto reductase family 1 member B10 (AKR1B10) is involved in tumour metabolic reprogramming; however, its role in LR remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Bioinformatics analyses of public databases were integrated and validated in established LR HCC cell lines. Functional assays (CCK-8, flow cytometry and Seahorse XF analysis) were performed to assess proliferation, apoptosis and aerobic glycolysis. Post-translational modifications of AKR1B10 were characterized using co-immunoprecipitation, mass spectrometry and western blot.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>AKR1B10 was identified as a critical driver of resistance by establishing a metabolic positive feedback loop. Bioinformatics analyses and experimental validation demonstrated that AKR1B10 upregulation correlates with therapeutic resistance. Functional studies indicated that AKR1B10 promotes resistance by enhancing aerobic glycolysis. Mechanistically, alanyl-tRNA synthetase 1 mediates lactylation modification at AKR1B10 lysine 173 (K173), stabilizing AKR1B10 by blocking ubiquitin (Ub)-proteasomal degradation. Stabilized AKR1B10 interacts physically with lactate dehydrogenase A (LDHA), promoting LDHA phosphorylation at Y10 and accelerating glycolytic lactate production. The increased lactate subsequently induces histone H3K18 lactylation (H3K18la), which transcriptionally upregulates LDHA expression. Thus, a self-reinforcing AKR1B10–lactate–LDHA amplification circuit is formed. Clinical analyses confirmed elevated AKR1B10 expression in LR HCC patient tissues. Importantly, targeting this axis with the AKR1B10 inhibitor epalrestat (EPA) synergized with lenvatinib, overcoming resistance in xenograft mouse models and patient-derived xenograft models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings establish AKR1B10 as both a biomarker and a therapeutic target in HCC. They reveal a novel lactylation-driven glycolytic adaptation mechanism and support the clinical translation of combined EPA–lenvatinib therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>AKR1B10 confers lenvatinib resistance by enhancing aerobic glycolysis in HCC cells.</li>\u0000 \u0000 <li>AKR1B10 undergoes AARS1-mediated lact","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12743142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Linshan Xie, Mengting Sun, Yujie Zheng, Zezhong Yu, Hui Kong, Jinjie Yu, Shaohua Lu, Yong Zhang, Jie Hu, Hongyi Xin, Jian Zhou, Xiangdong Wang, Charles A. Powell, Fred R. Hirsch, Chunxue Bai, Yuanlin Song, Jun Yin, Dawei Yang
<div> <section> <h3> Background</h3> <p>Early tumour vascular invasion contributes to cancer progression. Tip cells, a subset of tumour endothelial cells, significantly decline after anti-angiogenic therapy. However, their behaviour and the roles of their signature genes during early invasion are incompletely understood.</p> </section> <section> <h3> Methods</h3> <p>This study employed single-cell transcriptomic analysis and 10x Genomics Visium spatial transcriptomics on fresh lung tissues from patients with pulmonary nodules and from <i>Kras<sup>G12D</sup></i> (K) and <i>Kras<sup>G12D</sup>Tgfbr2<sup>−/−</sup></i> (KT) mice. The role of plasma vesicle-associated protein (PLVAP), a tip cell marker, was further examined using survival databases, immunofluorescence, in vitro co-culture, cell migration, invasion assays and endothelial tube formation.</p> </section> <section> <h3> Results</h3> <p>Tip cell proportions were elevated in early-stage lung adenocarcinoma (LUAD) tissues and KT mice, with evidence suggesting they arise from capillaries type I. PLVAP expression was enriched in tumour endothelial cells, induced by TGFβ1, and negatively correlated with patient prognosis. Functionally, PLVAP promoted endothelial cell invasion, migration and angiogenesis, and regulated tumour cell invasiveness. Intercellular analysis revealed that some tip cells also expressed TGFβ1, which may act on adjacent tumour cells to enhance invasion during early tumour development.</p> </section> <section> <h3> Conclusion</h3> <p>Tip cells increased during early LUAD progression and likely evolved from capillaries type I. Their marker PLVAP was associated with poor prognosis and pro-invasive endothelial behaviour. Tumour-secreted TGFβ1 upregulated PLVAP in endothelial cells, promoting angiogenesis and tumour invasion. Additionally, tip-cell-derived TGFβ1 may further stimulate tumour aggressiveness, highlighting a reciprocal interaction that contributes to early tumour progression.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li>Tip cells expand during early LUAD progression and likely originate from capillary type I endothelial cells.</li> <li>Tumour-derived TGFβ1 induces PLVAP expression in endothelial cells, linking tumour signals to vascular activation.</li> <li>PLVAP enhances endothelial cell migration, invasion
{"title":"PLVAP mediates the regulation of the tumour microenvironment in early-stage lung adenocarcinoma","authors":"Linshan Xie, Mengting Sun, Yujie Zheng, Zezhong Yu, Hui Kong, Jinjie Yu, Shaohua Lu, Yong Zhang, Jie Hu, Hongyi Xin, Jian Zhou, Xiangdong Wang, Charles A. Powell, Fred R. Hirsch, Chunxue Bai, Yuanlin Song, Jun Yin, Dawei Yang","doi":"10.1002/ctm2.70532","DOIUrl":"10.1002/ctm2.70532","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Early tumour vascular invasion contributes to cancer progression. Tip cells, a subset of tumour endothelial cells, significantly decline after anti-angiogenic therapy. However, their behaviour and the roles of their signature genes during early invasion are incompletely understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study employed single-cell transcriptomic analysis and 10x Genomics Visium spatial transcriptomics on fresh lung tissues from patients with pulmonary nodules and from <i>Kras<sup>G12D</sup></i> (K) and <i>Kras<sup>G12D</sup>Tgfbr2<sup>−/−</sup></i> (KT) mice. The role of plasma vesicle-associated protein (PLVAP), a tip cell marker, was further examined using survival databases, immunofluorescence, in vitro co-culture, cell migration, invasion assays and endothelial tube formation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Tip cell proportions were elevated in early-stage lung adenocarcinoma (LUAD) tissues and KT mice, with evidence suggesting they arise from capillaries type I. PLVAP expression was enriched in tumour endothelial cells, induced by TGFβ1, and negatively correlated with patient prognosis. Functionally, PLVAP promoted endothelial cell invasion, migration and angiogenesis, and regulated tumour cell invasiveness. Intercellular analysis revealed that some tip cells also expressed TGFβ1, which may act on adjacent tumour cells to enhance invasion during early tumour development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Tip cells increased during early LUAD progression and likely evolved from capillaries type I. Their marker PLVAP was associated with poor prognosis and pro-invasive endothelial behaviour. Tumour-secreted TGFβ1 upregulated PLVAP in endothelial cells, promoting angiogenesis and tumour invasion. Additionally, tip-cell-derived TGFβ1 may further stimulate tumour aggressiveness, highlighting a reciprocal interaction that contributes to early tumour progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Tip cells expand during early LUAD progression and likely originate from capillary type I endothelial cells.</li>\u0000 \u0000 <li>Tumour-derived TGFβ1 induces PLVAP expression in endothelial cells, linking tumour signals to vascular activation.</li>\u0000 \u0000 <li>PLVAP enhances endothelial cell migration, invasion","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 12","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12723075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Current vaccine platforms vary in their intrinsic strengths and limitations, making their suitability dependent on pathogen-specific features and the epidemiological setting. In the early phase of an outbreak, the ability to rapidly design, manufacture and implement a vaccine is essential. However, as the epidemic progresses – or when addressing endemic pathogens – the relative priorities may shift towards durability of protection, booster compatibility, manufacturability at global scale and affordability. Currently, no vaccine platform meets all these requirements, highlighting the need for continued innovation.</p><p>During the COVID-19 pandemic, messenger RNA (mRNA) vaccines proved their potential by enabling an exceptionally rapid vaccine rollout.<span><sup>1</sup></span> However, although these vaccines demonstrated high initial immunogenicity, the vaccine-induced neutralizing antibody titres declined rapidly, making repeated booster immunizations necessary to maintain protection.<span><sup>2</sup></span> Unfortunately, evidence suggest that the short antibody durability reflects an intrinsic property of the mRNA platform rather than an antigen-specific phenomenon.<span><sup>3</sup></span></p><p>In contrast, a single dose of a human papillomavirus capsid virus-like particle (cVLP) vaccine can provide long-lasting protection by inducing durable antibody responses.<span><sup>4</sup></span> This capacity for sustained humoral immunity is unique among subunit vaccines and is attributed to the dense, ordered, and repetitive epitope display characteristic of cVLPs, which efficiently drives robust germinal-centre reactions and long-lived plasma cell formation.<span><sup>5</sup></span></p><p>Supporting this concept, we previously developed a modular Tag/Catcher protein-based cVLP system that enabled the production of a non-adjuvanted COVID-19 vaccine which in a phase III clinical trial demonstrated non-inferiority to the licensed mRNA vaccine Comirnaty (NCT05329220). However, cVLP vaccines have similar manufacturing timelines as other protein-based vaccines, making frequent antigen updates to keep pace with emerging viral variants challenging.</p><p>Therefore, to combine the immunological properties of cVLPs with the manufacturing advantages of genetic vaccines, we developed a modular platform, in which co-delivery of gene sequences encoding the target antigen and a self-assembling cVLP enables in vivo formation of cVLP displaying the antigen at high density (Figure 1). Using the clinical-stage malaria transmission-blocking Pfs25 antigen as our model, we could demonstrate that this strategy enhances both humoral and cellular immunity, providing a dose sparing potential.</p><p>The platform is based on a genetically launched (mRNA or DNA) system encoding two components: a cVLP scaffold and a target antigen. Each component is genetically fused to a complementary split-protein (Tag or Catcher) binding partner, enabling spontaneous formation of covale
目前的疫苗平台在其内在优势和局限性方面各不相同，使其适用性取决于病原体特异性特征和流行病学环境。在疫情的早期阶段，快速设计、制造和实施疫苗的能力至关重要。然而，随着流行病的发展，或者在处理地方性病原体时，相对的优先事项可能会转向保护的持久性、增强剂的兼容性、在全球范围内的可制造性和可负担性。目前，没有任何疫苗平台能够满足所有这些要求，这突出了继续创新的必要性。在2019冠状病毒病大流行期间，信使RNA （mRNA）疫苗通过实现异常快速的疫苗推广，证明了其潜力然而，尽管这些疫苗显示出较高的初始免疫原性，但疫苗诱导的中和抗体滴度迅速下降，因此需要重复加强免疫以保持保护作用不幸的是，有证据表明，短抗体耐久性反映了mRNA平台的内在特性，而不是抗原特异性现象。相比之下，单剂量的人乳头瘤病毒衣壳病毒样颗粒（cVLP）疫苗可以通过诱导持久的抗体反应提供持久的保护这种持续体液免疫的能力在亚单位疫苗中是独一无二的，这归因于cVLPs密集、有序和重复的表位显示特征，这有效地驱动了强大的生发中心反应和长寿命的浆细胞形成。为了支持这一概念，我们之前开发了一种模块化的基于Tag/Catcher蛋白的cvpp系统，该系统能够生产一种无佐剂的COVID-19疫苗，该疫苗在III期临床试验中证明其不优于已获许可的mRNA疫苗Comirnaty （NCT05329220）。然而，cVLP疫苗与其他基于蛋白质的疫苗具有相似的生产时间表，这使得频繁的抗原更新以跟上新出现的病毒变体具有挑战性。因此，为了将cVLP的免疫学特性与基因疫苗的制造优势结合起来，我们开发了一个模块化平台，在该平台中，编码目标抗原的基因序列与自组装的cVLP共同递送，可以在体内形成高密度显示抗原的cVLP（图1）。使用临床阶段疟疾传播阻断Pfs25抗原作为我们的模型，我们可以证明这种策略增强了体液和细胞免疫，提供了剂量节约的潜力。该平台基于基因启动（mRNA或DNA）系统，编码两个组件：cVLP支架和靶抗原。每个成分在基因上融合到一个互补的分裂蛋白（标签或捕集器）结合伙伴，使cvpp和抗原之间自发形成共价键接种疫苗后，宿主细胞将这两种成分表达并组装成抗原修饰的cVLPs，最终分泌到细胞外空间。通过利用Tag/Catcher偶联系统，该方法提供了一个模块化的平台，使cVLP支架和抗原的不同组合能够混合和匹配，从而消除了为每个新靶标重新设计融合结构的需要。第一代mRNA疫苗通常以单体或最小多聚体形式表达抗原。然而，该系统能够以高度有序、重复和颗粒形式递送抗原，从而增强免疫反应的强度和潜在的持久性。Cyrielle Fougeroux和Adam F. Sander是一项专利申请的共同发明人，该专利申请涉及基于核酸的模块化cVLP疫苗平台（P5856PC00）的交付，并且是AdaptVac的股东，该公司开发并商业化VLP显示技术。
{"title":"A modular vaccine platform merging the rapid development of genetic vaccines with the immunogenicity of virus-like particles","authors":"Adam F. Sander, Cyrielle Fougeroux","doi":"10.1002/ctm2.70560","DOIUrl":"10.1002/ctm2.70560","url":null,"abstract":"<p>Current vaccine platforms vary in their intrinsic strengths and limitations, making their suitability dependent on pathogen-specific features and the epidemiological setting. In the early phase of an outbreak, the ability to rapidly design, manufacture and implement a vaccine is essential. However, as the epidemic progresses – or when addressing endemic pathogens – the relative priorities may shift towards durability of protection, booster compatibility, manufacturability at global scale and affordability. Currently, no vaccine platform meets all these requirements, highlighting the need for continued innovation.</p><p>During the COVID-19 pandemic, messenger RNA (mRNA) vaccines proved their potential by enabling an exceptionally rapid vaccine rollout.<span><sup>1</sup></span> However, although these vaccines demonstrated high initial immunogenicity, the vaccine-induced neutralizing antibody titres declined rapidly, making repeated booster immunizations necessary to maintain protection.<span><sup>2</sup></span> Unfortunately, evidence suggest that the short antibody durability reflects an intrinsic property of the mRNA platform rather than an antigen-specific phenomenon.<span><sup>3</sup></span></p><p>In contrast, a single dose of a human papillomavirus capsid virus-like particle (cVLP) vaccine can provide long-lasting protection by inducing durable antibody responses.<span><sup>4</sup></span> This capacity for sustained humoral immunity is unique among subunit vaccines and is attributed to the dense, ordered, and repetitive epitope display characteristic of cVLPs, which efficiently drives robust germinal-centre reactions and long-lived plasma cell formation.<span><sup>5</sup></span></p><p>Supporting this concept, we previously developed a modular Tag/Catcher protein-based cVLP system that enabled the production of a non-adjuvanted COVID-19 vaccine which in a phase III clinical trial demonstrated non-inferiority to the licensed mRNA vaccine Comirnaty (NCT05329220). However, cVLP vaccines have similar manufacturing timelines as other protein-based vaccines, making frequent antigen updates to keep pace with emerging viral variants challenging.</p><p>Therefore, to combine the immunological properties of cVLPs with the manufacturing advantages of genetic vaccines, we developed a modular platform, in which co-delivery of gene sequences encoding the target antigen and a self-assembling cVLP enables in vivo formation of cVLP displaying the antigen at high density (Figure 1). Using the clinical-stage malaria transmission-blocking Pfs25 antigen as our model, we could demonstrate that this strategy enhances both humoral and cellular immunity, providing a dose sparing potential.</p><p>The platform is based on a genetically launched (mRNA or DNA) system encoding two components: a cVLP scaffold and a target antigen. Each component is genetically fused to a complementary split-protein (Tag or Catcher) binding partner, enabling spontaneous formation of covale","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 12","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12723062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<div> <section> <h3> Background</h3> <p>As a critical component of the tumour microenvironment, cancer-associated fibroblasts (CAFs) actively drive the malignant advancement of non-small-cell lung cancer (NSCLC); however, their underlying mechanisms continue to be poorly characterized. This work examined the role of CAFs-derived exosomal miR-3126-5p in the glycolysis of NSCLC cells.</p> </section> <section> <h3> Methods</h3> <p>Glycolysis was evaluated by lactate production, glucose uptake, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Cell proliferation and cycle were evaluated by CCK-8, EdU staining, and flow cytometry. Src homology 2B adaptor protein 1 (SH2B1) and insulin receptor substrate 1 (IRS1) protein interaction was tested by Co-IP and GST pull-down assay. ChIP, dual-luciferase reporter assay, and EMSA determined the binding of kruppel-like factor 13 (KLF13) to the SH2B1 promoter. Dual-luciferase reporter assay was applied to assess miR-3126-5p binding to KLF13 3′-UTR. In vivo growth of NSCLC was determined in the mouse xenograft and Lewis lung carcinoma models.</p> </section> <section> <h3> Results</h3> <p>CAFs-derived exosomal miR-3126-5p was highly expressed in NSCLC tissues, and its elevated plasma level was significantly associated with poor prognosis of NSCLC patients. CAFs-derived exosomal miR-3126-5p facilitated glycolysis to accelerate the malignant progression of NSCLC cells. KLF13 exhibited reduced expression in NSCLC, while its overexpression suppressed NSCLC growth via repressing glycolysis. Exosomal miR-3126-5p targeted KLF13 3′-UTR to inhibit its expression in NSCLC cells. KLF13 transcriptionally inhibited SH2B1 expression to abolish the interaction between SH2B1 and IRS1 proteins, thus repressing PI3K/AKT pathway-mediated glycolysis. KLF13 knockdown counteracted the anti-cancer action of exosomal miR-3126-5p inhibition.</p> </section> <section> <h3> Conclusion</h3> <p>CAFs-derived exosomal miR-3126-5p accelerated NSCLC progression via inhibiting KLF13 expression, which transcriptionally activated SH2B1 to promote its interaction with IRS1, thereby promoting PI3K/AKT pathway-mediated glycolysis. Our findings position CAFs-secreted exosomal miR-3126-5p as a novel therapeutic intervention with potential in NSCLC management.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>CAFs-derived exosomal miR-3126-5p enhanced glycolysis
{"title":"Exosomal miR-3126-5p derived from cancer-associated fibroblasts facilitates glycolysis to accelerate NSCLC progression by targeting KLF13 to activate the SH2B1/IRS1 axis","authors":"Zhenyu Zhang, Haicheng Ma, Yingying Zheng, Lina Wang, Chenghui Wang, Yuanyuan Liu, Hengxiao Lu, Shaoqiang Wang","doi":"10.1002/ctm2.70554","DOIUrl":"10.1002/ctm2.70554","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>As a critical component of the tumour microenvironment, cancer-associated fibroblasts (CAFs) actively drive the malignant advancement of non-small-cell lung cancer (NSCLC); however, their underlying mechanisms continue to be poorly characterized. This work examined the role of CAFs-derived exosomal miR-3126-5p in the glycolysis of NSCLC cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Glycolysis was evaluated by lactate production, glucose uptake, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Cell proliferation and cycle were evaluated by CCK-8, EdU staining, and flow cytometry. Src homology 2B adaptor protein 1 (SH2B1) and insulin receptor substrate 1 (IRS1) protein interaction was tested by Co-IP and GST pull-down assay. ChIP, dual-luciferase reporter assay, and EMSA determined the binding of kruppel-like factor 13 (KLF13) to the SH2B1 promoter. Dual-luciferase reporter assay was applied to assess miR-3126-5p binding to KLF13 3′-UTR. In vivo growth of NSCLC was determined in the mouse xenograft and Lewis lung carcinoma models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>CAFs-derived exosomal miR-3126-5p was highly expressed in NSCLC tissues, and its elevated plasma level was significantly associated with poor prognosis of NSCLC patients. CAFs-derived exosomal miR-3126-5p facilitated glycolysis to accelerate the malignant progression of NSCLC cells. KLF13 exhibited reduced expression in NSCLC, while its overexpression suppressed NSCLC growth via repressing glycolysis. Exosomal miR-3126-5p targeted KLF13 3′-UTR to inhibit its expression in NSCLC cells. KLF13 transcriptionally inhibited SH2B1 expression to abolish the interaction between SH2B1 and IRS1 proteins, thus repressing PI3K/AKT pathway-mediated glycolysis. KLF13 knockdown counteracted the anti-cancer action of exosomal miR-3126-5p inhibition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>CAFs-derived exosomal miR-3126-5p accelerated NSCLC progression via inhibiting KLF13 expression, which transcriptionally activated SH2B1 to promote its interaction with IRS1, thereby promoting PI3K/AKT pathway-mediated glycolysis. Our findings position CAFs-secreted exosomal miR-3126-5p as a novel therapeutic intervention with potential in NSCLC management.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>CAFs-derived exosomal miR-3126-5p enhanced glycolysis ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 12","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12712867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yan Zhang, Cheng Tao, Xiteng Yin, Zhi Wang, Yuyang Zhang, Jiale Yu, Yufeng Wang, Wei Han
<div> <section> <h3> Background</h3> <p>The worst pattern of invasion (WPOI) is a critical histological prognostic indicator in oral squamous cell carcinoma (OSCC), yet the underlying mechanisms driving high WPOI remain poorly understood. While cancer-associated fibroblasts (CAFs) and their secreted factor serglycin (SRGN) are implicated in tumour progression, the regulation of SRGN secretion within the hypoxic tumour microenvironment is unknown.</p> </section> <section> <h3> Methods</h3> <p>We performed single-cell RNA sequencing (scRNA-seq) on 6 OSCC samples (3 each of WPOI 1–3 and 4–5) to identify subgroups of CAFs and their characteristic gene expression profiles. Using Western blot, qRT-PCR, and immunofluorescence, we investigated hypoxia-induced SRGN secretion pathways. Complementary CRISPR-Cas9 knockout, Co-IP assays, and xenograft models elucidated SRGN's role in ECM remodelling.</p> </section> <section> <h3> Results</h3> <p>ScRNA-seq revealed significant enrichment of CAFs, particularly an SRGN-expressing myCAF subpopulation, in high-WPOI (4–5) OSCC tissues. Under hypoxia, CAFs switched SRGN secretion from the conventional ER-Golgi pathway to an unconventional secretory autophagy pathway, dependent on autophagosome formation but independent of lysosomal degradation. Secreted SRGN directly interacted with matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) in the extracellular matrix (ECM), enhancing ECM remodelling and OSCC invasion and migration. In vivo, either genetic ablation of SRGN in CAFs or pharmacological inhibition of autophagy significantly suppressed tumour growth, inhibited collagen I degradation, and restored E-cadherin expression.</p> </section> <section> <h3> Conclusion</h3> <p>Our study identifies a novel mechanism whereby hypoxia induces CAFs to secrete SRGN via secretory autophagy. This SRGN-MMP2/9 axis drives ECM remodelling and promotes OSCC invasion, which histologically manifests as high WPOI. Targeting secretory autophagy or SRGN represents a promising therapeutic strategy for aggressive OSCC.</p> </section> <section> <h3> Key points</h3> <div> <ol> <li> <p>Under normoxia, SRGN enters the conventional secretory pathway via the endoplasmic reticulum (ER) and Golgi apparatus for extracellular release.</p> </li> <li> <p>Under hyp
{"title":"Hypoxia-induced secretory autophagy in cancer-associated fibroblasts promotes ECM remodelling through serglycin secretion in oral squamous cell carcinoma","authors":"Yan Zhang, Cheng Tao, Xiteng Yin, Zhi Wang, Yuyang Zhang, Jiale Yu, Yufeng Wang, Wei Han","doi":"10.1002/ctm2.70556","DOIUrl":"10.1002/ctm2.70556","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The worst pattern of invasion (WPOI) is a critical histological prognostic indicator in oral squamous cell carcinoma (OSCC), yet the underlying mechanisms driving high WPOI remain poorly understood. While cancer-associated fibroblasts (CAFs) and their secreted factor serglycin (SRGN) are implicated in tumour progression, the regulation of SRGN secretion within the hypoxic tumour microenvironment is unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed single-cell RNA sequencing (scRNA-seq) on 6 OSCC samples (3 each of WPOI 1–3 and 4–5) to identify subgroups of CAFs and their characteristic gene expression profiles. Using Western blot, qRT-PCR, and immunofluorescence, we investigated hypoxia-induced SRGN secretion pathways. Complementary CRISPR-Cas9 knockout, Co-IP assays, and xenograft models elucidated SRGN's role in ECM remodelling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>ScRNA-seq revealed significant enrichment of CAFs, particularly an SRGN-expressing myCAF subpopulation, in high-WPOI (4–5) OSCC tissues. Under hypoxia, CAFs switched SRGN secretion from the conventional ER-Golgi pathway to an unconventional secretory autophagy pathway, dependent on autophagosome formation but independent of lysosomal degradation. Secreted SRGN directly interacted with matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) in the extracellular matrix (ECM), enhancing ECM remodelling and OSCC invasion and migration. In vivo, either genetic ablation of SRGN in CAFs or pharmacological inhibition of autophagy significantly suppressed tumour growth, inhibited collagen I degradation, and restored E-cadherin expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study identifies a novel mechanism whereby hypoxia induces CAFs to secrete SRGN via secretory autophagy. This SRGN-MMP2/9 axis drives ECM remodelling and promotes OSCC invasion, which histologically manifests as high WPOI. Targeting secretory autophagy or SRGN represents a promising therapeutic strategy for aggressive OSCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ol>\u0000 \u0000 <li>\u0000 <p>Under normoxia, SRGN enters the conventional secretory pathway via the endoplasmic reticulum (ER) and Golgi apparatus for extracellular release.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Under hyp","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 12","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12712735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hongliang Xie, Yu Lu, Aolin Zhang, Anqi Zheng, Baofeng Rao, Cuiyu Yang, Anyao Li, Wenbo Guo, Linhua Hu, Xiaoling Huang, Chi Chiu Wang, Songying Zhang, Xiaohui Fan, Lu Li
Background
Advanced maternal age (AMA) increases pregnancy risk. However, uterine-specific mechanisms independent of oocyte and embryo quality remain poorly defined. This study aimed to characterise the decidual microenvironment in women with AMA to identify key pathological changes and regulatory pathways.
Methods and results
Through integrated histology, organoid modelling, and high-resolution scRNA-seq of first-trimester decidua from women of AMA and controlled reproductive age, we uncovered a pathologically remodelled decidual microenvironment characterised by aberrant cellular states and pathological differentiation pathways, leading to a pro-fibrotic state and accompanied by immune cell dysfunction, and disrupted intercellular communication in the AMA decidua. Central to this pathology was hyperactivated TGF-β signalling, driving fibroblast-to-myofibroblast transition and extracellular matrix overproduction, thereby fuelling fibrosis. Aberrant TGF-β further impaired decidual stromal cell (DSC) differentiation, leading to the failure of the essential mesenchymal-to-epithelial transition. We identified PRR15 as a novel DSC-specific regulator that is markedly suppressed in AMA. PRR15 deficiency unleashed hyperactive TGF-β/SMAD signalling, directly causing decidualisation failure, enhanced fibrosis, and aborted DSC differentiation. Epithelial–mesenchymal transition and immune cell reprogramming towards pro-fibrotic transcriptional signatures further amplify the fibrotic pathology.
Conclusion
This study established the aged decidual microenvironment, orchestrated by dysregulated TGF-β signalling and PRR15 loss, as a critical independent determinant of reproductive failure in AMA. Thus, it unveils novel diagnostic and therapeutic targets and strategies.
Key points
We provide the first single-cell atlas of the human decidua in advanced maternal age (AMA).
A novel PRR15-TGF-β axis is identified, where PRR15 loss drives stromal fibrosis and decidualisation failure.
This study reveals that AMA-associated uterine fibrosis begins in the first trimester, shifting focus to maternal factors.
{"title":"Single-cell transcriptome analyses reveal disturbed decidual microenvironment in women of advanced maternal age","authors":"Hongliang Xie, Yu Lu, Aolin Zhang, Anqi Zheng, Baofeng Rao, Cuiyu Yang, Anyao Li, Wenbo Guo, Linhua Hu, Xiaoling Huang, Chi Chiu Wang, Songying Zhang, Xiaohui Fan, Lu Li","doi":"10.1002/ctm2.70541","DOIUrl":"10.1002/ctm2.70541","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Advanced maternal age (AMA) increases pregnancy risk. However, uterine-specific mechanisms independent of oocyte and embryo quality remain poorly defined. This study aimed to characterise the decidual microenvironment in women with AMA to identify key pathological changes and regulatory pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and results</h3>\u0000 \u0000 <p>Through integrated histology, organoid modelling, and high-resolution scRNA-seq of first-trimester decidua from women of AMA and controlled reproductive age, we uncovered a pathologically remodelled decidual microenvironment characterised by aberrant cellular states and pathological differentiation pathways, leading to a pro-fibrotic state and accompanied by immune cell dysfunction, and disrupted intercellular communication in the AMA decidua. Central to this pathology was hyperactivated TGF-β signalling, driving fibroblast-to-myofibroblast transition and extracellular matrix overproduction, thereby fuelling fibrosis. Aberrant TGF-β further impaired decidual stromal cell (DSC) differentiation, leading to the failure of the essential mesenchymal-to-epithelial transition. We identified PRR15 as a novel DSC-specific regulator that is markedly suppressed in AMA. PRR15 deficiency unleashed hyperactive TGF-β/SMAD signalling, directly causing decidualisation failure, enhanced fibrosis, and aborted DSC differentiation. Epithelial–mesenchymal transition and immune cell reprogramming towards pro-fibrotic transcriptional signatures further amplify the fibrotic pathology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study established the aged decidual microenvironment, orchestrated by dysregulated TGF-β signalling and PRR15 loss, as a critical independent determinant of reproductive failure in AMA. Thus, it unveils novel diagnostic and therapeutic targets and strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>We provide the first single-cell atlas of the human decidua in advanced maternal age (AMA).</li>\u0000 \u0000 <li>A novel PRR15-TGF-β axis is identified, where PRR15 loss drives stromal fibrosis and decidualisation failure.</li>\u0000 \u0000 <li>This study reveals that AMA-associated uterine fibrosis begins in the first trimester, shifting focus to maternal factors.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 12","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12711380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chaomeng Wang, Yan Yang, Wei Wang, Liyan Li, Mengting Che, Yingying Chen, Honglei Wang, Zhaoyun Liu, Lijuan Li, Hui Liu, Rong Fu
Background
Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal haematopoietic stem cell disorder. Immune escape is crucial in PNH, and our previous studies revealed that natural killer (NK) cells potential participate in the immune escape of PNH. This study aimed to investigate the subtypes and functional changes of NK cells in PNH patients.
Methods
We analysed CD59+ and CD59− bone marrow mononuclear cells using single-cell RNA sequencing (scRNA-seq). The results were validated through flow cytometry and co-culture experiments.
Results
We classified NK cells into seven subtypes by scRNA-seq, and found significant differences in the distribution of subtypes in CD59+ and CD59− NK cell of PNH patients. Compared with controls, the proportion of active and adaptive NK cells was higher in CD59+ NK cells. Conversely, the proportion of CD56bright NK cells and terminal NK cells was elevated in CD59− NK cells. Additionally, the proportion of mature NK cells decreased in both the CD59+ and CD59− groups. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis revealed impaired function of CD59− NK cells, whereas CD59+ NK cells showed minimal change. Furthermore, similar results were verified by flow cytometry and co-culture in vivo and in vitro. And the proportion of NK cells was closely related to the proportion of CD8+ T cells and the clinical indicators of disease.
Conclusions
The quantity and function of NK cells in PNH patients are insufficient, in which CD59− NK cells have functional defects, whereas CD59+ NK cells were mainly activated and potential involved in immune escape by regulation of T cells.
{"title":"Role of NK cells in immune escape in patients with classical paroxysmal nocturnal haemoglobinuria","authors":"Chaomeng Wang, Yan Yang, Wei Wang, Liyan Li, Mengting Che, Yingying Chen, Honglei Wang, Zhaoyun Liu, Lijuan Li, Hui Liu, Rong Fu","doi":"10.1002/ctm2.70542","DOIUrl":"10.1002/ctm2.70542","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal haematopoietic stem cell disorder. Immune escape is crucial in PNH, and our previous studies revealed that natural killer (NK) cells potential participate in the immune escape of PNH. This study aimed to investigate the subtypes and functional changes of NK cells in PNH patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analysed CD59<sup>+</sup> and CD59<sup>−</sup> bone marrow mononuclear cells using single-cell RNA sequencing (scRNA-seq). The results were validated through flow cytometry and co-culture experiments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We classified NK cells into seven subtypes by scRNA-seq, and found significant differences in the distribution of subtypes in CD59<sup>+</sup> and CD59<sup>−</sup> NK cell of PNH patients. Compared with controls, the proportion of active and adaptive NK cells was higher in CD59<sup>+</sup> NK cells. Conversely, the proportion of CD56<sup>bright</sup> NK cells and terminal NK cells was elevated in CD59<sup>−</sup> NK cells. Additionally, the proportion of mature NK cells decreased in both the CD59<sup>+</sup> and CD59<sup>−</sup> groups. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis revealed impaired function of CD59<sup>−</sup> NK cells, whereas CD59<sup>+</sup> NK cells showed minimal change. Furthermore, similar results were verified by flow cytometry and co-culture in vivo and in vitro. And the proportion of NK cells was closely related to the proportion of CD8<sup>+</sup> T cells and the clinical indicators of disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The quantity and function of NK cells in PNH patients are insufficient, in which CD59<sup>−</sup> NK cells have functional defects, whereas CD59<sup>+</sup> NK cells were mainly activated and potential involved in immune escape by regulation of T cells.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 12","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12710432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145767037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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