Weifeng Wang, Yuxiang Deng, Weihao Li, Ruowei Wang, Chi Zhou, Yanbo Xu, Jiahua He, Le' en Liao, Jin Lan, Long Yu, Da Kang, Weili Zhang, Qingjian Ou, Zhizhong Pan, Yujing Fang, Peirong Ding, Junzhong Lin, Jianhong Peng
<div> <section> <h3> Background</h3> <p>TROP2, a critical cell surface oncogenic signal transducer, is increasingly linked to refractory metastatic colorectal cancer (CRC) and other solid tumours. Robust lactate accumulation within metastatic niches correlates with pathological metastatic progression. Anti-TROP2 antibody-drug conjugates (ADCs) are clinically available but show limited efficacy in advanced metastatic CRC. Elucidating how TROP2 signalling orchestrates molecular and cellular programs enabling CRC metastatic progression would help improve metastasis therapies.</p> </section> <section> <h3> Methods</h3> <p>Tissue microarray, immunohistochemistry, and western blotting delineated TROP2's pathological role in CRC liver metastasis (CRLM). Metabolomics characterised TROP2-mediated metabolic effect. Western blot detected TROP2 responsive lactylation sites. Cell-derived xenograft (CDX), intra-splenic injection models, and patient-derived xenografts (PDX) validated TROP2 or TROP2-induced H3K18 lactylation (H3K18la) in CRLM pathogenesis and Acriflavine therapeutic response. Genome-wide H3K18la profiling was performed by ChIP-seq.</p> </section> <section> <h3> Results</h3> <p>Here, we identify a self-reinforcing positive feedback loop between H3K18la and TROP2 in CRC cells that drives CRC metastatic progression. We show that TROP2 is elevated during CRC metastatic process, with high TROP2 levels in liver metastases predicting increased post-therapy recurrence in two distinct cohorts. We find that H3K18la levels are upregulated in CRC cells in response to TROP2 expression level. TROP2 promotes robust lactate production via the YBX1-HIF-1α signal axis. Targeting glycolytic flux decreases H3K18 lactylation and curbs TROP2-driven CRLM colonisation and progression. Mechanistically, ChIP-seq detection reveals H3K18la deposition at a set of pro-metastatic gene promoters, promoting their expression. Crucially, TROP2-induced H3K18la is found in turn sustaining TROP2 expression, forming a positive feedback loop that further accelerated metastatic progression. Pharmacologic HIF-1α inhibition with acriflavine, an old FDA-approved agent, suppresses TROP2-high CRLM progression in multiple pre-clinical models.</p> </section> <section> <h3> Conclusions</h3> <p>Collectively, we establish H3K18la as a crucial epigenetic driver of TROP2-mediated CRLM progression and propose that disrupting the H3K18la–TROP2 feedback loop offers a novel therapeutic strategy against CRC metastasis.</p> </section> <section>
{"title":"Feedback regulation between histone H3 lysine 18 lactylation and TROP2-mediated glycolysis drives metastatic progression of colorectal cancer","authors":"Weifeng Wang, Yuxiang Deng, Weihao Li, Ruowei Wang, Chi Zhou, Yanbo Xu, Jiahua He, Le' en Liao, Jin Lan, Long Yu, Da Kang, Weili Zhang, Qingjian Ou, Zhizhong Pan, Yujing Fang, Peirong Ding, Junzhong Lin, Jianhong Peng","doi":"10.1002/ctm2.70562","DOIUrl":"10.1002/ctm2.70562","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>TROP2, a critical cell surface oncogenic signal transducer, is increasingly linked to refractory metastatic colorectal cancer (CRC) and other solid tumours. Robust lactate accumulation within metastatic niches correlates with pathological metastatic progression. Anti-TROP2 antibody-drug conjugates (ADCs) are clinically available but show limited efficacy in advanced metastatic CRC. Elucidating how TROP2 signalling orchestrates molecular and cellular programs enabling CRC metastatic progression would help improve metastasis therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Tissue microarray, immunohistochemistry, and western blotting delineated TROP2's pathological role in CRC liver metastasis (CRLM). Metabolomics characterised TROP2-mediated metabolic effect. Western blot detected TROP2 responsive lactylation sites. Cell-derived xenograft (CDX), intra-splenic injection models, and patient-derived xenografts (PDX) validated TROP2 or TROP2-induced H3K18 lactylation (H3K18la) in CRLM pathogenesis and Acriflavine therapeutic response. Genome-wide H3K18la profiling was performed by ChIP-seq.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Here, we identify a self-reinforcing positive feedback loop between H3K18la and TROP2 in CRC cells that drives CRC metastatic progression. We show that TROP2 is elevated during CRC metastatic process, with high TROP2 levels in liver metastases predicting increased post-therapy recurrence in two distinct cohorts. We find that H3K18la levels are upregulated in CRC cells in response to TROP2 expression level. TROP2 promotes robust lactate production via the YBX1-HIF-1α signal axis. Targeting glycolytic flux decreases H3K18 lactylation and curbs TROP2-driven CRLM colonisation and progression. Mechanistically, ChIP-seq detection reveals H3K18la deposition at a set of pro-metastatic gene promoters, promoting their expression. Crucially, TROP2-induced H3K18la is found in turn sustaining TROP2 expression, forming a positive feedback loop that further accelerated metastatic progression. Pharmacologic HIF-1α inhibition with acriflavine, an old FDA-approved agent, suppresses TROP2-high CRLM progression in multiple pre-clinical models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Collectively, we establish H3K18la as a crucial epigenetic driver of TROP2-mediated CRLM progression and propose that disrupting the H3K18la–TROP2 feedback loop offers a novel therapeutic strategy against CRC metastasis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12761367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892160","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>Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by high mortality with no specific treatments. Fibroblast growth factor 10 (FGF10) is recognized for its tissue repair and anti-inflammatory roles in injured lungs; however, its clinical relevance and mechanistic role in ARDS remain unclear.</p> </section> <section> <h3> Methods</h3> <p>Serum FGF10 levels were measured in patients with ARDS and analyzed for associations with clinical outcomes. An LPS-induced mouse model of acute lung injury (ALI) was used to evaluate the effects of FGF10 treatment in vivo. Single-cell RNA sequencing of lineage-traced alveolar epithelial cells (AECs) was performed to identify transcriptional changes following FGF10 administration. In vitro co-culture systems involving macrophages or neutrophils with AECs were established to investigate immune cell-specific mechanisms.</p> </section> <section> <h3> Results</h3> <p>We found that serum FGF10 levels were significantly reduced in ARDS patients, and this reduction correlated with poor prognosis. Moreover, FGF10 treatment alleviated lung inflammation by decreasing inflammatory cell infiltration and pro-inflammatory cytokine release in mice. Leveraging single-cell RNA sequencing of lineage tracing alveolar epithelial cells (AECs), we identified that the mRNA expression of <i>Ripk1</i>, <i>Casp8</i>, and <i>Casp3</i> were decreased after FGF10 treatment. In in vitro co-culture experiments, we noticed that FGF10 did not inhibit macrophage pyroptosis. Instead, FGF10 effectively blocked the downstream RIPK1/caspase-8/caspase-3/gasdermin E (GSDME) signaling pathway in AECs. Additionally, FGF10 suppressed AMP-activated protein kinase (AMPK) activation by modulating ATP production, thereby preventing RIPK1 cleavage.</p> </section> <section> <h3> Conclusion</h3> <p>FGF10 alleviates acute lung injury by inhibiting AMPK-RIPK1/caspase-8/caspase-3/GSDME-mediated pyroptosis in AECs primed by distinct immune cell populations, supporting its potential as a therapeutic strategy for ARDS.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li>Our study reveals a marked decrease of serum FGF10 levels in ARDS patients, correlating with P/F ratio, hospitalisation days and mortality rates.</li> <li>We clarify how FGF10 prevents AECs' pyroptosis triggered by di
背景：急性呼吸窘迫综合征（ARDS）是一种危及生命的疾病，其特点是死亡率高，无特异性治疗。成纤维细胞生长因子10 （FGF10）在肺损伤中具有组织修复和抗炎作用；然而，其在ARDS中的临床相关性和机制作用尚不清楚。方法：检测ARDS患者血清FGF10水平，并分析其与临床结局的关系。采用lps诱导的小鼠急性肺损伤（ALI）模型，在体内评价FGF10的治疗效果。对谱系追踪的肺泡上皮细胞（AECs）进行单细胞RNA测序，以确定FGF10给药后的转录变化。建立了巨噬细胞或中性粒细胞与aec体外共培养系统，以研究免疫细胞特异性机制。结果：我们发现ARDS患者血清FGF10水平显著降低，且这种降低与预后不良相关。此外，FGF10治疗通过降低小鼠炎症细胞浸润和促炎细胞因子释放来减轻肺部炎症。利用对肺泡上皮细胞（AECs）进行谱系追踪的单细胞RNA测序，我们发现FGF10处理后，Ripk1、Casp8和Casp3的mRNA表达降低。在体外共培养实验中，我们注意到FGF10没有抑制巨噬细胞的焦亡。相反，FGF10在aec中有效阻断了下游RIPK1/caspase-8/caspase-3/gasdermin E （GSDME）信号通路。此外，FGF10通过调节ATP的产生抑制amp活化蛋白激酶（AMPK）的激活，从而阻止RIPK1的裂解。结论：FGF10通过抑制AMPK-RIPK1/caspase-8/caspase-3/ gsdme介导的AECs焦亡，减轻急性肺损伤，支持其作为ARDS治疗策略的潜力。重点：我们的研究显示ARDS患者血清FGF10水平显著下降，与P/F比、住院天数和死亡率相关。我们阐明了FGF10如何以不同的方式阻止不同免疫细胞浸润引发的aec焦亡。FGF10恢复ATP水平，通过AMPK减弱RIPK1磷酸化，破坏aec的焦亡。
{"title":"Roll with the punches: Fibroblast growth factor 10 alleviates pyroptosis of alveolar epithelial cells in different immune niches","authors":"Tianchang Wei, Xiaoyan Chen, Jian Xu, Weiqi Mao, Zhenlin Yang, Yuhan Wang, Yufan Li, Wenting Jin, Cuicui Chen, Cuiping Zhang, Yuanlin Song","doi":"10.1002/ctm2.70569","DOIUrl":"10.1002/ctm2.70569","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by high mortality with no specific treatments. Fibroblast growth factor 10 (FGF10) is recognized for its tissue repair and anti-inflammatory roles in injured lungs; however, its clinical relevance and mechanistic role in ARDS remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Serum FGF10 levels were measured in patients with ARDS and analyzed for associations with clinical outcomes. An LPS-induced mouse model of acute lung injury (ALI) was used to evaluate the effects of FGF10 treatment in vivo. Single-cell RNA sequencing of lineage-traced alveolar epithelial cells (AECs) was performed to identify transcriptional changes following FGF10 administration. In vitro co-culture systems involving macrophages or neutrophils with AECs were established to investigate immune cell-specific mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that serum FGF10 levels were significantly reduced in ARDS patients, and this reduction correlated with poor prognosis. Moreover, FGF10 treatment alleviated lung inflammation by decreasing inflammatory cell infiltration and pro-inflammatory cytokine release in mice. Leveraging single-cell RNA sequencing of lineage tracing alveolar epithelial cells (AECs), we identified that the mRNA expression of <i>Ripk1</i>, <i>Casp8</i>, and <i>Casp3</i> were decreased after FGF10 treatment. In in vitro co-culture experiments, we noticed that FGF10 did not inhibit macrophage pyroptosis. Instead, FGF10 effectively blocked the downstream RIPK1/caspase-8/caspase-3/gasdermin E (GSDME) signaling pathway in AECs. Additionally, FGF10 suppressed AMP-activated protein kinase (AMPK) activation by modulating ATP production, thereby preventing RIPK1 cleavage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>FGF10 alleviates acute lung injury by inhibiting AMPK-RIPK1/caspase-8/caspase-3/GSDME-mediated pyroptosis in AECs primed by distinct immune cell populations, supporting its potential as a therapeutic strategy for ARDS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Our study reveals a marked decrease of serum FGF10 levels in ARDS patients, correlating with P/F ratio, hospitalisation days and mortality rates.</li>\u0000 \u0000 <li>We clarify how FGF10 prevents AECs' pyroptosis triggered by di","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12759039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892130","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}
This study investigates the impact of sleep restriction (SR) on flap viability and its underlying mechanisms. It reveals that SR triggers clock rhythmic ferroptosis, which leads to impaired skin barrier function and increased flap necrosis.
Methods
A retrospective analysis of sleep quality in 344 patients undergoing flap surgery proved that SR is a risk factor for flap necrosis. Further research demonstrated that SR increases the level of ferroptosis, disrupts the circadian rhythm of ferroptosis and exacerbates flap damage in human and murine models.
Results
In order to address this clinical issue, the use of melatonin (MT)-preconditioned bone marrow mesenchymal stromal cells-derived exosomes (MEXOs) was found to enhance the therapeutic efficacy of flap repair by mitigating clock rhythmic ferroptosis. Mechanistically, MT increased m6A modification to stabilise and enhance the translation of ubiquitin-specific protease 4 (USP4) mRNA within MEXOs. USP4 delivered by MEXOs directly interacted with and deubiquitinated ARNTL, a core circadian regulator, stabilising its protein levels and suppressing ferroptosis in flap.
Conclusions
These findings identify SR-induced clock rhythmic ferroptosis as a critical pathological driver of flap failure and propose a novel exosome-based strategy targeting the USP4–ARNTL axis to enhance skin barrier integrity and flap survival, offering translational potential for clinical reconstructive surgery.
Key points
This study identifies SR-induced clock rhythmic ferroptosis as a pivotal pathological process in flap necrosis.
We reveal a potential therapeutic mechanism in which USP4-enriched MEXOs can effectively repair SR-induced flap necrosis.
USP4-enriched MEXOs represent a novel therapy for SR-induced flap necrosis by stabilizing ARNTL to inhibit clock rhythmic ferroptosis.
{"title":"Melatonin-engineered MSCs-exosomes deliver USP4 to stabilise ARNTL and inhibit clock rhythmic ferroptosis for enhanced flap survival","authors":"Xiaoqiong Jiang, Yu Wang, Xuanlong Zhang, Huiming Deng, Liangyu Fang, Chaire Tafadzwa, Jiangnan Yao, Hao Chen, Anqi Ye, Kailiang Zhou, Xiangwei Ling, Jian Xiao","doi":"10.1002/ctm2.70565","DOIUrl":"10.1002/ctm2.70565","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>This study investigates the impact of sleep restriction (SR) on flap viability and its underlying mechanisms. It reveals that SR triggers clock rhythmic ferroptosis, which leads to impaired skin barrier function and increased flap necrosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A retrospective analysis of sleep quality in 344 patients undergoing flap surgery proved that SR is a risk factor for flap necrosis. Further research demonstrated that SR increases the level of ferroptosis, disrupts the circadian rhythm of ferroptosis and exacerbates flap damage in human and murine models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In order to address this clinical issue, the use of melatonin (MT)-preconditioned bone marrow mesenchymal stromal cells-derived exosomes (MEXOs) was found to enhance the therapeutic efficacy of flap repair by mitigating clock rhythmic ferroptosis. Mechanistically, MT increased m6A modification to stabilise and enhance the translation of ubiquitin-specific protease 4 (USP4) mRNA within MEXOs. USP4 delivered by MEXOs directly interacted with and deubiquitinated ARNTL, a core circadian regulator, stabilising its protein levels and suppressing ferroptosis in flap.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings identify SR-induced clock rhythmic ferroptosis as a critical pathological driver of flap failure and propose a novel exosome-based strategy targeting the USP4–ARNTL axis to enhance skin barrier integrity and flap survival, offering translational potential for clinical reconstructive surgery.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ol>\u0000 \u0000 <li>\u0000 <p>This study identifies SR-induced clock rhythmic ferroptosis as a pivotal pathological process in flap necrosis.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>We reveal a potential therapeutic mechanism in which USP4-enriched MEXOs can effectively repair SR-induced flap necrosis.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>USP4-enriched MEXOs represent a novel therapy for SR-induced flap necrosis by stabilizing ARNTL to inhibit clock rhythmic ferroptosis.</p>\u0000 </li>\u0000 </ol>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12759045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892132","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}
Wang D, Ruan X, Liu X, et al. SUMOylation of PUM2 promotes the vasculogenic mimicry of glioma cells via regulating CEBPD. Clin Transl Med. 2020;10(5):e168. doi:10.1002/ctm2.168
[Description of error]
In Figure 2g, the image of the U251 control group was inadvertently taken from an earlier draft version rather than the finalised version. Consequently, the control group image may appear to display a slightly higher apparent cell density compared with the sh-NC group, which could lead to a minor visual misinterpretation.
After carefully re-examining all original data, we confirmed that this mistake was due to the incorrect selection of a representative image for the control group. Therefore, this correction does not alter the results, statistical analyses, or conclusions of the paper.
The corrected version of Figure 2g is provided below. We sincerely apologise for this oversight and for any confusion it may have caused.
{"title":"Correction to ‘SUMOylation of PUM2 promotes the vasculogenic mimicry of glioma cells via regulating CEBPD’","authors":"","doi":"10.1002/ctm2.70559","DOIUrl":"10.1002/ctm2.70559","url":null,"abstract":"<p>Wang D, Ruan X, Liu X, et al. SUMOylation of PUM2 promotes the vasculogenic mimicry of glioma cells via regulating CEBPD. <i>Clin Transl Med</i>. 2020;10(5):e168. doi:10.1002/ctm2.168</p><p><b>[Description of error]</b></p><p>In Figure 2g, the image of the U251 control group was inadvertently taken from an earlier draft version rather than the finalised version. Consequently, the control group image may appear to display a slightly higher apparent cell density compared with the sh-NC group, which could lead to a minor visual misinterpretation.</p><p>After carefully re-examining all original data, we confirmed that this mistake was due to the incorrect selection of a representative image for the control group. Therefore, this correction does not alter the results, statistical analyses, or conclusions of the paper.</p><p>The corrected version of Figure 2g is provided below. We sincerely apologise for this oversight and for any confusion it may have caused.</p><p></p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12759038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892091","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}
Melanie Seaton, Sarah Harbach, Joanne Oke, Thomas D. J. Walker, Jessica Dalton-O'Reilly, Julian Selley, Daniel R. Brison, James Bolton, Stefan Meyer, David Knight, Richard J. Edmondson, Christine K. Schmidt
<p>Dear Editor,</p><p>Most high-grade serous ovarian cancer (HGSOC) cases arise from pre-invasive fallopian tube (FT) lesions, known as serous tubal intraepithelial carcinomas (STICs). Yet, despite an estimated 6- to 7-year window-of-opportunity, no clinical test exists for detecting these at an early, treatable stage.<span><sup>1</sup></span> To address this, we developed and applied a novel sampling technique to obtain FT lavage, enabling analysis of early tumour-associated molecular changes in FT-derived biofluids.</p><p>To establish the feasibility of this technique, we collected 27 FT lavages from high-risk <i>BRCA1/2</i> mutation carriers, ovarian neoplasm (ON) patients, and control individuals with benign or non-tubal gynaecological conditions (Figure 1A and B; Supplementary Discussions 1 and 2). Lavages were acquired from FTs directly after surgical removal by inserting a PBS-filled syringe into the FT lumen beyond the fimbrial end and flushing towards the utero-tubal junction (Figure 2A). Sampling away from the fimbriae enabled us to test for signals diffusing from any lesions proximally along the tube, where they would be accessible via minimally invasive trans-cervical falloposcopy,<span><sup>2</sup></span> supporting potential clinical feasibility (Supplementary Discussion 3).</p><p>As FTs were flushed post-surgical removal, effects of blood contamination on downstream analysis were reduced through selective depletion of common blood proteins during sample preparation (Figure 2A), and removal of abundant plasma proteins during analysis (Figure S1). Proteomic analysis revealed > 2000 proteins per sample with significant overlap between samples (Figure S1a and b, Table S1), including FT-resident mucins (MUC16/CA125, MUC5B, MUC5AC) and oviduct-specific glycoprotein 1 (OVGP1). No major differences in the numbers of the top 400 plasma proteins detected were identified between samples (mean ± SD = 316 ± 13.2), and this was proportionally slight (8.7%) compared to overall protein numbers (Figure S1a). Intra-patient comparison showed strong correlation between left and right FT samples for most pairs (<i>R</i><sup>2 </sup>>0.9, Figure S2a–d), overall indicating FT lavage as a promising resource for comparative proteomic analysis across risk and disease states.</p><p>To assess the ability of FT lavage to distinguish between neoplastic and non-neoplastic samples, we compared proteomes of a left and right FT lavage from a patient with a unilateral ovarian neoplasm (MFC6), thereby controlling for inter-patient variability and confounding factors. Despite high overall correlation (<i>R</i><sup>2 </sup>= 0.9933), several tumour-promoting proteins were enriched in the neoplasm-associated FT, such as SPTAN1, which is overexpressed in early OC lesions in the FT,<span><sup>3</sup></span> while tumour suppressor fructose-1,6-bisphosphatase 1 (FBP1)<span><sup>4</sup></span> was reduced (Figure 2B, Table S2), suggesting that our workflow has potenti
{"title":"Fallopian tube lavage sampling towards early detection of pre-invasive ovarian cancer","authors":"Melanie Seaton, Sarah Harbach, Joanne Oke, Thomas D. J. Walker, Jessica Dalton-O'Reilly, Julian Selley, Daniel R. Brison, James Bolton, Stefan Meyer, David Knight, Richard J. Edmondson, Christine K. Schmidt","doi":"10.1002/ctm2.70557","DOIUrl":"10.1002/ctm2.70557","url":null,"abstract":"<p>Dear Editor,</p><p>Most high-grade serous ovarian cancer (HGSOC) cases arise from pre-invasive fallopian tube (FT) lesions, known as serous tubal intraepithelial carcinomas (STICs). Yet, despite an estimated 6- to 7-year window-of-opportunity, no clinical test exists for detecting these at an early, treatable stage.<span><sup>1</sup></span> To address this, we developed and applied a novel sampling technique to obtain FT lavage, enabling analysis of early tumour-associated molecular changes in FT-derived biofluids.</p><p>To establish the feasibility of this technique, we collected 27 FT lavages from high-risk <i>BRCA1/2</i> mutation carriers, ovarian neoplasm (ON) patients, and control individuals with benign or non-tubal gynaecological conditions (Figure 1A and B; Supplementary Discussions 1 and 2). Lavages were acquired from FTs directly after surgical removal by inserting a PBS-filled syringe into the FT lumen beyond the fimbrial end and flushing towards the utero-tubal junction (Figure 2A). Sampling away from the fimbriae enabled us to test for signals diffusing from any lesions proximally along the tube, where they would be accessible via minimally invasive trans-cervical falloposcopy,<span><sup>2</sup></span> supporting potential clinical feasibility (Supplementary Discussion 3).</p><p>As FTs were flushed post-surgical removal, effects of blood contamination on downstream analysis were reduced through selective depletion of common blood proteins during sample preparation (Figure 2A), and removal of abundant plasma proteins during analysis (Figure S1). Proteomic analysis revealed > 2000 proteins per sample with significant overlap between samples (Figure S1a and b, Table S1), including FT-resident mucins (MUC16/CA125, MUC5B, MUC5AC) and oviduct-specific glycoprotein 1 (OVGP1). No major differences in the numbers of the top 400 plasma proteins detected were identified between samples (mean ± SD = 316 ± 13.2), and this was proportionally slight (8.7%) compared to overall protein numbers (Figure S1a). Intra-patient comparison showed strong correlation between left and right FT samples for most pairs (<i>R</i><sup>2 </sup>>0.9, Figure S2a–d), overall indicating FT lavage as a promising resource for comparative proteomic analysis across risk and disease states.</p><p>To assess the ability of FT lavage to distinguish between neoplastic and non-neoplastic samples, we compared proteomes of a left and right FT lavage from a patient with a unilateral ovarian neoplasm (MFC6), thereby controlling for inter-patient variability and confounding factors. Despite high overall correlation (<i>R</i><sup>2 </sup>= 0.9933), several tumour-promoting proteins were enriched in the neoplasm-associated FT, such as SPTAN1, which is overexpressed in early OC lesions in the FT,<span><sup>3</sup></span> while tumour suppressor fructose-1,6-bisphosphatase 1 (FBP1)<span><sup>4</sup></span> was reduced (Figure 2B, Table S2), suggesting that our workflow has potenti","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12759042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892126","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>DDB1 and CUL4-associated factor 7 (DCAF7) is a WD-repeat adaptor that recruits substrates to the CUL4DDB1 ubiquitinligase complex, but its pan-cancer relevance and mechanistic contribution to tumor progression remain unclear.</p> </section> <section> <h3> Methods</h3> <p>Multi-omics datasets (genomic, transcriptomic, epigenomic, proteomic and single-cell) from 33 tumor types were integrated to define DCAF7 expression, regulation, and clinical significance. Somatic alterations and copy-number variation were analysed across cohorts, and promoter methylation and RNA modification signatures were interrogated. Immune associations were assessed by computational deconvolution and checkpoint-gene profiling. Pathway and network analyses were performed to infer DCAF7-linked programmes. Mechanistic and functional validation was conducted in hepatocellular carcinoma (LIHC) cell lines (HepG2, Huh7) using DCAF7 perturbation and pharmacologic Wnt inhibition.</p> </section> <section> <h3> Results</h3> <p>DCAF7 was overexpressed in most cancers, consistent with copy-number gain, focal promoter hypomethylation and putative m<sup>6</sup>A-linked post-transcriptional regulation, whereas hypermethylation at two CpG loci predicted poor prognosis in LIHC. DCAF7 alterations, predominantly amplifications, were associated with shorter overall survival in LIHC and positively correlated with DCAF7 mRNA abundance across cohorts. Immunogenomic analyses linked high DCAF7 to CD4<sup>+</sup> T-cell enrichment, broad upregulation of checkpoint genes (PD-1/PD-L1, CTLA-4, TIGIT), and increased tumour mutational burden, microsatellite instability and neoantigen load, suggesting an immune-evasive phenotype. Network and enrichment analyses converged on canonical Wnt/β-catenin, Hippo and cell-cycle programs. In vitro, DCAF7 promoted LIHC cell proliferation and migration by stabilising β-catenin via increased inhibitory Ser9 phosphorylation of GSK-3β, thereby inducing c-Myc and cyclin D1; DCAF7 knockdown or the Wnt inhibitor XAV939 attenuated these effects. Drug-response modelling further predicted increased sensitivity of DCAF7-high tumours to 17-AAG, docetaxel and alsterpaullone.</p> </section> <section> <h3> Conclusions</h3> <p>DCAF7 is frequently activated by genetic and epigenetic mechanisms across cancers, associates with an immunotherapy-relevant tumour immune milieu, and drives Wnt/β-catenindependent malignant phenotypes in LIHC. These findings support DCAF7 as a prognostic biomarker and a candidate therapeutic target, particularly for strat
{"title":"Pan-cancer multi-omics reveals DCAF7 as an immune-modulating prognostic driver and Wnt/β-catenin activator in hepatocellular carcinoma","authors":"Ruina Luan, Hanbin Lin, Xin Zhao, Jianpeng Li, Maohe Chen, Shiping Luo, Xinjian Lin","doi":"10.1002/ctm2.70572","DOIUrl":"10.1002/ctm2.70572","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>DDB1 and CUL4-associated factor 7 (DCAF7) is a WD-repeat adaptor that recruits substrates to the CUL4DDB1 ubiquitinligase complex, but its pan-cancer relevance and mechanistic contribution to tumor progression remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Multi-omics datasets (genomic, transcriptomic, epigenomic, proteomic and single-cell) from 33 tumor types were integrated to define DCAF7 expression, regulation, and clinical significance. Somatic alterations and copy-number variation were analysed across cohorts, and promoter methylation and RNA modification signatures were interrogated. Immune associations were assessed by computational deconvolution and checkpoint-gene profiling. Pathway and network analyses were performed to infer DCAF7-linked programmes. Mechanistic and functional validation was conducted in hepatocellular carcinoma (LIHC) cell lines (HepG2, Huh7) using DCAF7 perturbation and pharmacologic Wnt inhibition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>DCAF7 was overexpressed in most cancers, consistent with copy-number gain, focal promoter hypomethylation and putative m<sup>6</sup>A-linked post-transcriptional regulation, whereas hypermethylation at two CpG loci predicted poor prognosis in LIHC. DCAF7 alterations, predominantly amplifications, were associated with shorter overall survival in LIHC and positively correlated with DCAF7 mRNA abundance across cohorts. Immunogenomic analyses linked high DCAF7 to CD4<sup>+</sup> T-cell enrichment, broad upregulation of checkpoint genes (PD-1/PD-L1, CTLA-4, TIGIT), and increased tumour mutational burden, microsatellite instability and neoantigen load, suggesting an immune-evasive phenotype. Network and enrichment analyses converged on canonical Wnt/β-catenin, Hippo and cell-cycle programs. In vitro, DCAF7 promoted LIHC cell proliferation and migration by stabilising β-catenin via increased inhibitory Ser9 phosphorylation of GSK-3β, thereby inducing c-Myc and cyclin D1; DCAF7 knockdown or the Wnt inhibitor XAV939 attenuated these effects. Drug-response modelling further predicted increased sensitivity of DCAF7-high tumours to 17-AAG, docetaxel and alsterpaullone.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>DCAF7 is frequently activated by genetic and epigenetic mechanisms across cancers, associates with an immunotherapy-relevant tumour immune milieu, and drives Wnt/β-catenindependent malignant phenotypes in LIHC. These findings support DCAF7 as a prognostic biomarker and a candidate therapeutic target, particularly for strat","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12754573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145862350","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}
Jianfei Zhu, Yanlu Xiong, Shouzheng Ma, Jun Wei, Jiakuan Chen, Wenchen Wang, Qianqian Duan, Qin Zhang, Dongsheng Chen, Wanglong Deng, Tao Jiang, Jie Lei
<div> <section> <h3> Background</h3> <p>Primary pulmonary sarcomas (PPS) and pulmonary sarcomatoid carcinoma (PSC) are rare and aggressive diseases that pose significant diagnostic challenges, requiring extensive sampling and comprehensive evaluation. To date, the single-cell characteristics and distinctions between these two conditions have not been thoroughly investigated.</p> </section> <section> <h3> Methods</h3> <p>In this study, we employed single-nucleus RNA sequencing (snRNA-seq) to characterise the cellular heterogeneity of PSC and PPS. Our analysis included 20 PSC samples, seven PPS samples and two non-malignant control samples obtained from adjacent normal tissue.</p> </section> <section> <h3> Results</h3> <p>Our results revealed that the majority of cells in PSC were of epithelial origin, while fibroblasts predominated in PPS. Specifically, AT2 cells, a major source of epithelial cells in PSC, underwent malignant transformation primarily through epithelial–mesenchymal transition, suggesting AT2 cells may serve as the origin of PSC. High Mobility Group AT-Hook 2 (HMGA2) expression was elevated in malignant AT2 cells of PSC and correlated with an unfavourable prognosis. Moreover, MET-mutated patients have a significantly higher expression level of HMGA2 (<i>p</i> < .001). In PPS, fibroblasts constituted the majority, only lipofibroblasts exhibited malignant features. A direct comparison between PSC and PPS lipofibroblasts revealed largely similar expression profiles, with the exception of an enrichment in DNA repair pathways specifically observed in PPS lipofibroblasts.</p> </section> <section> <h3> Conclusion</h3> <p>These findings provide novel insights of PSC and PPS at the single-cell level.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li><b>Distinct Cellular Origins</b>: PSC arises primarily from epithelial (AT2) cells via EMT, whereas PPS is predominantly fibroblast-derived.</li> <li><b>Prognostic Driver HMGA2</b>: Elevated HMGA2 in malignant AT2 cells correlates with poor prognosis and is significantly higher in MET-mutated PSC.</li> <li><b>Pathway Divergence in Malignant Cells</b>: Malignant lipofibroblasts in PPS share a similar profile with PSC but uniquely enrich DNA repair pathways.</li> </ul> </div> </section>
{"title":"Single-nucleus RNA sequencing reveals the distinct heterogeneity of primary pulmonary sarcomas (PPS) and pulmonary sarcomatoid carcinoma (PSC)","authors":"Jianfei Zhu, Yanlu Xiong, Shouzheng Ma, Jun Wei, Jiakuan Chen, Wenchen Wang, Qianqian Duan, Qin Zhang, Dongsheng Chen, Wanglong Deng, Tao Jiang, Jie Lei","doi":"10.1002/ctm2.70566","DOIUrl":"10.1002/ctm2.70566","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Primary pulmonary sarcomas (PPS) and pulmonary sarcomatoid carcinoma (PSC) are rare and aggressive diseases that pose significant diagnostic challenges, requiring extensive sampling and comprehensive evaluation. To date, the single-cell characteristics and distinctions between these two conditions have not been thoroughly investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we employed single-nucleus RNA sequencing (snRNA-seq) to characterise the cellular heterogeneity of PSC and PPS. Our analysis included 20 PSC samples, seven PPS samples and two non-malignant control samples obtained from adjacent normal tissue.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our results revealed that the majority of cells in PSC were of epithelial origin, while fibroblasts predominated in PPS. Specifically, AT2 cells, a major source of epithelial cells in PSC, underwent malignant transformation primarily through epithelial–mesenchymal transition, suggesting AT2 cells may serve as the origin of PSC. High Mobility Group AT-Hook 2 (HMGA2) expression was elevated in malignant AT2 cells of PSC and correlated with an unfavourable prognosis. Moreover, MET-mutated patients have a significantly higher expression level of HMGA2 (<i>p</i> < .001). In PPS, fibroblasts constituted the majority, only lipofibroblasts exhibited malignant features. A direct comparison between PSC and PPS lipofibroblasts revealed largely similar expression profiles, with the exception of an enrichment in DNA repair pathways specifically observed in PPS lipofibroblasts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings provide novel insights of PSC and PPS at the single-cell level.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li><b>Distinct Cellular Origins</b>: PSC arises primarily from epithelial (AT2) cells via EMT, whereas PPS is predominantly fibroblast-derived.</li>\u0000 \u0000 <li><b>Prognostic Driver HMGA2</b>: Elevated HMGA2 in malignant AT2 cells correlates with poor prognosis and is significantly higher in MET-mutated PSC.</li>\u0000 \u0000 <li><b>Pathway Divergence in Malignant Cells</b>: Malignant lipofibroblasts in PPS share a similar profile with PSC but uniquely enrich DNA repair pathways.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12753329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145862379","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}
{"title":"CLINICAL AND TRANSLATIONAL MEDICINE","authors":"","doi":"10.1002/ctm2.70585","DOIUrl":"https://doi.org/10.1002/ctm2.70585","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70585","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145891093","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}
Lu Chen, Chunluan Yuan, Teng Yu, Kaiyuan Hui, Xiuming Li, Xiaozhu Shen, Xiaodong Jiang, Bin Liu
<div> <section> <h3> Background</h3> <p>Colorectal adenocarcinoma (COAD) cells exploit stress-adaptation programs, such as the unfolded protein response (UPR), to survive in hostile tumour microenvironments. However, the role of specific E3 ubiquitin ligases in regulating these survival pathways remains poorly understood. We investigated Ring Finger Protein 39 (RNF39), an E3 ligase previously implicated in immune signalling, as a potential regulator of COAD progression.</p> </section> <section> <h3> Methods</h3> <p>We analyzed RNF39 expression using public transcriptomic datasets (TCGA, GEO) and a clinical COAD cohort via immunohistochemistry. Functional roles were assessed in COAD cell lines using shRNA knockdown, CRISPR/Cas9 knockout, and overexpression systems. In vitro assays (proliferation, invasion, colony formation) and in vivo xenograft models were employed. Mechanistic investigations included co-immunoprecipitation, ubiquitination assays, chromatin immunoprecipitation, and luciferase reporter assays to delineate the MEF2D-RNF39-RINT1 axis.</p> </section> <section> <h3> Results</h3> <p>RNF39 was aberrantly upregulated in COAD tissues, and its high expression correlated with poor patient survival. We identified the transcription factor MEF2D as a direct activator of RNF39. Functionally, RNF39 promoted COAD cell proliferation and invasion in vitro and tumour growth in vivo, dependent on its E3 ligase activity. Mechanistically, RNF39 directly interacted with, polyubiquitinated (K48-linked), and promoted the proteasomal degradation of RAD50-interacting protein 1 (RINT1). Consequently, RNF39 depletion stabilized RINT1, amplified the UPR and CHOP expression, and sensitized cells to ER stress-induced apoptosis. Crucially, the anti-tumour phenotypes of RNF39 loss were partially reversed by simultaneous RINT1 knockdown.</p> </section> <section> <h3> Conclusion</h3> <p>RNF39 acts as a pro-tumorigenic E3 ligase in COAD by driving the degradation of RINT1, thereby suppressing ER stress-induced apoptosis and promoting malignant progression. Our findings delineate a novel MEF2D-RNF39-RINT1 signalling axis that governs tumour cell adaptation to stress. Targeting RNF39 could represent a promising therapeutic strategy to overcome stress resistance in COAD.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li>RNF39 is identified as an oncogenic E3 ubiquitin ligase that is upregulated in col
{"title":"RNF39 promotes colorectal cancer progression by driving RINT1 degradation and suppressing ER stress-induced apoptosis","authors":"Lu Chen, Chunluan Yuan, Teng Yu, Kaiyuan Hui, Xiuming Li, Xiaozhu Shen, Xiaodong Jiang, Bin Liu","doi":"10.1002/ctm2.70577","DOIUrl":"10.1002/ctm2.70577","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Colorectal adenocarcinoma (COAD) cells exploit stress-adaptation programs, such as the unfolded protein response (UPR), to survive in hostile tumour microenvironments. However, the role of specific E3 ubiquitin ligases in regulating these survival pathways remains poorly understood. We investigated Ring Finger Protein 39 (RNF39), an E3 ligase previously implicated in immune signalling, as a potential regulator of COAD progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed RNF39 expression using public transcriptomic datasets (TCGA, GEO) and a clinical COAD cohort via immunohistochemistry. Functional roles were assessed in COAD cell lines using shRNA knockdown, CRISPR/Cas9 knockout, and overexpression systems. In vitro assays (proliferation, invasion, colony formation) and in vivo xenograft models were employed. Mechanistic investigations included co-immunoprecipitation, ubiquitination assays, chromatin immunoprecipitation, and luciferase reporter assays to delineate the MEF2D-RNF39-RINT1 axis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>RNF39 was aberrantly upregulated in COAD tissues, and its high expression correlated with poor patient survival. We identified the transcription factor MEF2D as a direct activator of RNF39. Functionally, RNF39 promoted COAD cell proliferation and invasion in vitro and tumour growth in vivo, dependent on its E3 ligase activity. Mechanistically, RNF39 directly interacted with, polyubiquitinated (K48-linked), and promoted the proteasomal degradation of RAD50-interacting protein 1 (RINT1). Consequently, RNF39 depletion stabilized RINT1, amplified the UPR and CHOP expression, and sensitized cells to ER stress-induced apoptosis. Crucially, the anti-tumour phenotypes of RNF39 loss were partially reversed by simultaneous RINT1 knockdown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>RNF39 acts as a pro-tumorigenic E3 ligase in COAD by driving the degradation of RINT1, thereby suppressing ER stress-induced apoptosis and promoting malignant progression. Our findings delineate a novel MEF2D-RNF39-RINT1 signalling axis that governs tumour cell adaptation to stress. Targeting RNF39 could represent a promising therapeutic strategy to overcome stress resistance in COAD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>RNF39 is identified as an oncogenic E3 ubiquitin ligase that is upregulated in col","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12745170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848857","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}
Laura E. Kane, Croí E. Buckley, Rebecca M. O'Brien, Meghana S. Menon, Aisling B. Heeran, Xiaofei Yin, Timothy S. Nugent, Noel E. Donlon, John V Reynolds, Adnan Hafeez, Diarmuid S. O'Ríordáin, Robert A. Hannon, Paul Neary, Reza Kalbassi, Brian J. Mehigan, Paul H. McCormick, Cara Dunne, John O. Larkin, Lorraine Brennan, Michael E. Kelly, Jacintha O'Sullivan, Niamh Lynam-Lennon
<p>Dear Editor,</p><p>Rectal cancer (RC) incidence is rising, particularly in individuals < 50 years, who present with aggressive, treatment-refractory tumours.<span><sup>1</sup></span> Resistance to neoadjuvant treatment (neo-tx) is a significant problem, with no biomarkers of response currently in use. Tumours of similar clinical characteristics can have vastly different responses to neo-tx, suggesting the dichotomy in response is due to differences in the tumour molecular environment. Alterations in mitochondrial function and energy metabolism play a role in the pathogenesis of gastrointestinal cancers,<span><sup>2, 3</sup></span> implicating the metabolome as a potential untapped source of predictive biomarkers. To address this unmet need, we performed multi-omic analysis of metabolomic and transcriptomic profiles from normal, non-cancer rectal tissue and pre-treatment RC biopsies (Supporting Information) to identify alterations associated with the pathogenesis of RC.</p><p>Liquid chromatography-mass spectrometry revealed 29 metabolites significantly altered in RC tissue (<i>n </i>= 32) compared to non-cancer rectal tissue (<i>n </i>= 20) (Figure 1A). Pathway analysis uncovered 65 upregulated and four downregulated pathways significantly associated with altered metabolites (Figure 1B). Most altered metabolites were lipid molecules or mediators of lipid metabolism, suggesting that remodelling of lipid metabolism is a feature of RC. Diacyl phosphatidylcholines (PCs) are important mediators of lipid metabolism, supporting other studies highlighting a role for choline metabolism and lipid remodelling in tumourigenesis.<span><sup>4</sup></span> SM C18:0 and SM (OH) C22:1 are sphingolipids, important structural lipid components of biological membranes, which support the physiological function of the colon and are deregulated in RC.<span><sup>5</sup></span> Interestingly, cancer cells hydrolyse sphingomyelin to maintain production of PCs,<span><sup>4</sup></span> suggesting a mechanism for the concomitant increase in PCs and decrease in sphingomyelins demonstrated in RC here.</p><p>Real-time metabolic analysis demonstrated that (Figure 1C)OCR rates and OCR/ECAR ratios were significantly decreased in RC compared to non-cancer rectal tissue, highlighting metabolic remodelling in RC. Inhibition of mitochondrial metabolism results in accelerated turnover of PCs in neuronal cells,<span><sup>6</sup></span> suggesting a mechanism underlying the altered choline metabolism demonstrated in RC.</p><p>Transcriptomics revealed 2337 genes differentially expressed between RC (<i>n </i>= 31) and non-cancer rectal tissue (<i>n </i>= 28) (Figure 1D). Pathway analysis revealed 41 upregulated and seven downregulated pathways significantly associated with altered genes (Figure 1E). Interestingly, several of the most altered genes play roles in mitochondrial respiration. <i>ND2</i>, <i>ND3</i> and <i>ND5</i> encode subunits of the NADH dehydrogenase enzyme, a crucial
亲爱的编辑，直肠癌（RC）的发病率正在上升，特别是在50岁以上的个体中，他们表现出侵袭性，难治性肿瘤对新辅助治疗（neo-tx）的耐药是一个重要的问题，目前还没有生物标志物的反应。临床特征相似的肿瘤可能对neo-tx有截然不同的反应，这表明反应的二分法是由于肿瘤分子环境的差异。线粒体功能和能量代谢的改变在胃肠道癌症的发病机制中发挥作用，2,3暗示代谢组是一种潜在的未开发的预测性生物标志物来源。为了解决这一未满足的需求，我们对正常、非癌性直肠组织和治疗前直肠癌活检的代谢组学和转录组学进行了多组学分析，以确定与直肠癌发病机制相关的改变。液相色谱-质谱分析显示，与非癌直肠组织（n = 20）相比，癌组织中有29种代谢物显著改变（n = 32）（图1A）。通路分析发现65条上调通路和4条下调通路与代谢产物改变显著相关（图1B）。大多数改变的代谢物是脂质分子或脂质代谢介质，这表明脂质代谢的重塑是RC的一个特征。二酰基磷脂酰胆碱（PCs）是脂质代谢的重要介质，支持其他研究强调胆碱代谢和脂质重塑在肿瘤发生中的作用SM C18:0和SM (OH) C22:1是鞘脂，是生物膜的重要结构脂质成分，支持结肠的生理功能，在RC中不受调节。有趣的是，癌细胞水解鞘磷脂以维持pc的产生，这表明在RC中证明了pc同时增加和鞘磷脂减少的机制。实时代谢分析显示（图1C），与非癌性直肠组织相比，癌性直肠组织的OCR率和OCR/ECAR比值显著降低，突出了癌性直肠组织的代谢重塑。线粒体代谢的抑制导致神经元细胞中pc的更新加速，6这表明在RC中证实了胆碱代谢改变的机制。转录组学显示，有2337个基因在直肠癌组织（n = 31）和非癌直肠组织（n = 28）之间存在差异表达（图1D）。通路分析显示41条上调通路和7条下调通路与基因改变显著相关（图1E）。有趣的是，一些改变最多的基因在线粒体呼吸中起作用。ND2， ND3和ND5编码NADH脱氢酶的亚基，NADH脱氢酶是电子传递链的关键组成部分，支持在RC组织中显示的改变的OCR。在治疗前的RC活检中，改变的代谢物与OCR、ECAR、OCR/ECAR比值以及几个临床变量（包括改进的Ryan肿瘤反应评分（TRS））有显著相关性（TRS1 =完全缓解，TRS1 =接近完全缓解，TRS2 =部分缓解）（图2A）。两种代谢物与TRS显著相关：血清素和lysoPC a C16:1（图2B）。无监督分层聚类在TRS2中显示出良好的分组，TRS0和TRS1之间几乎没有区别，表明两者之间的表达谱相似（图2C）。只有lysoPC a C16:1与临床变量有显著相关性（图2D）。SLC6A4在CRC组织中的表达，其转录5 -羟色胺，对无复发生存无显著影响（图2E），而SLC6A4的低表达导致进展后生存显著恶化（图2F）。5 -羟色胺可增强结肠癌患者的放射敏感性，7提示TRS2患者血清素降低是neo-tx耐药的机制之一。改变的基因与几个临床变量有显著相关性（图3A）。RPL30和CXCL14在TRS2中显著上调，而SNORA81、SNORD50A、LCN2和SNORA64在TRS2中与TRS0相比显著下调（图3B）。RPL30的表达增加与癌基因MYC的扩增有关，从而促进细胞毒性治疗的耐药性在一些癌症中，SNORD50A的缺失与较差的生存结果相关有趣的是，SNORD50A结合并抑制癌基因KRAS， SNORD50A的耗尽导致MAPK级联的激活，9参与肿瘤对治疗的耐药，10提示在RC中neo-tx耐药的潜在作用。基于基因表达的TRS分离得到了改进，TRS0和TRS2区分明显（图3C）。一些基因与临床变量有显著相关性（图3D）。低CXCL14表达与总体（图3E）和进展后生存期（图3F）明显较差相关。 高RPL30与较长的总生存期显著相关（图3G）；然而，它导致无复发生存（图3H）和进展后生存（图3I）显著恶化，这与TRS2患者的高RPL30一致。同样，低LCN2表达与较差的总生存率相关（图3J）。改变的基因和代谢物被整合到一个8个特征的多组学生物标志物面板中。由于没有匹配的TRS3患者转录组数据，只有TRS0 （n = 3）、TRS1 （n = 6）和TRS2 （n = 5）组可以纳入最终分析。TRS0和TRS2分别使用这8个特征进行聚类，TRS1分布在它们之间（图4A）。主成分分析显示了类似的模式，血清素、SNORA64、SNORD50A、SNORA81、RPL30和CXCL14对组分离的贡献最大（图4B）。单独检查各特征的表达情况，TRS0和TRS2的单独特征表达水平较高，而TRS1位于TRS0和TRS2的范围内（图4C）。留一交叉验证表明，TRS0与TRS1/TRS2的区别较差（曲线下面积[AUC] = 0.273，灵敏度= 0%，特异性= 54.5%），可能是由于组间样本的不平衡（TRS0 = 3, TRS1/TRS2 = 11），因此不能准确地代表这些组间面板的性能（图4D）。与TRS2相比，TRS0的分类准确率要高得多（AUC = 0.933，灵敏度= 100%，特异性= 80%），这与观察到的不同表达谱一致（图4B，C）。最后，在该试点队列中，TRS0/TRS1与TRS2表现出完美的分类（AUC = 1, Sensitivity = 100%, Specificity = 100%），表明总体而言，TRS2患者的表达谱与TRS0和TRS1不同，两者之间的关系更为密切（图4D）。在一个试点队列中，我们证明直肠肿瘤具有代谢和转录组重塑，强调脂质代谢改变是直肠肿瘤的共同特征，提出了一种新的治疗靶向方法。我们还确定了一个新的多组学8-生物标志物面板，在代表全TRS谱的独立队列验证后，有潜力作为neo-tx病理反应的预测标志，以改善患者分层。劳拉e凯恩：数据策展，正式分析和写作-原始草案。Croí E. Buckley：调查，数据管理和形式分析。丽贝卡·M. o .布莱恩：数据管理和资源。Meghana S. Menon：数据管理和资源。Aisling B. Heeran：数据管理和资源。尹晓飞：调查与形式分析。Timothy S. Nugent：临床样本和临床数据。Noel E. Donlon：临床样本和临床数据。约翰·v·雷诺兹：资源。Adnan Hafeez：临床样本。Diarmuid S. O.R-ordáin：临床样本。Robert A. Hannon：临床样本。Paul Neary：临床样本。Reza Kalbassi：临床样本。Brian J. Mehigan：临床样本。Paul H. McCormick：临床样本。卡拉·邓恩：临床样本。John O. Larkin：临床样本。洛林·布伦南：形式分析和写作——审查和编辑。迈克尔E.凯利：临床样本，临床数据和写作-审查和编辑。贾辛塔O.沙利文：概念，监督和写作-审查和编辑。概念化、监督、资金获取、写作。原稿和写作-审查和编辑。作者声明无利益冲突。这项研究由卫生研究委员会（爱尔兰）资助，资助号：EIA-2017-020。我们也感谢SFI研究基础设施计划下的综合分子分析平台（CMAP）的资助，参考编号：18/RI/5702。勒。凯恩得到了爱尔兰研究基
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