Pub Date : 2025-07-11DOI: 10.1016/j.neo.2025.101207
Kirsten Brooksbank , Charlotte Smith , Eleni Maniati , Amy Gibson , Wai Yiu Tse , Amy Kate Hall , Jun Wang , Tyson V Sharp , Sarah A Martin
Immune checkpoint inhibitors (ICIs) are extremely effective in a subgroup of mismatch repair-deficient (MMRd) cancers, but ∼50% remain resistant to treatment. We have shown for the first time that this may be due to the differential regulation of factors linked to response to ICIs upon loss of the different MMR genes. Here, we show that increased PD-L1 expression is observed upon loss of the MMR genes MLH1, MSH2 and PMS2. However, this is not true upon loss of MSH6, and we show that this is due to a novel role for MSH6 as a direct regulator of PD-L1 transcription, dependent on recruitment by the histone trimethyltransferase SETD2. Next-generation sequencing of MLH1 and MSH6 knockout (KO) cells revealed that MSH6 KO cells have significantly lower microsatellite instability in comparison to MLH1 KO cells, despite MSH6 KO cells having a higher mutational burden. These findings emphasise the need for gene-specific stratification in the MMRd cohort.
{"title":"The DNA mismatch repair protein, MSH6 is a novel regulator of PD-L1 expression","authors":"Kirsten Brooksbank , Charlotte Smith , Eleni Maniati , Amy Gibson , Wai Yiu Tse , Amy Kate Hall , Jun Wang , Tyson V Sharp , Sarah A Martin","doi":"10.1016/j.neo.2025.101207","DOIUrl":"10.1016/j.neo.2025.101207","url":null,"abstract":"<div><div>Immune checkpoint inhibitors (ICIs) are extremely effective in a subgroup of mismatch repair-deficient (MMRd) cancers, but ∼50% remain resistant to treatment. We have shown for the first time that this may be due to the differential regulation of factors linked to response to ICIs upon loss of the different MMR genes. Here, we show that increased PD-L1 expression is observed upon loss of the MMR genes MLH1, MSH2 and PMS2. However, this is not true upon loss of MSH6, and we show that this is due to a novel role for MSH6 as a direct regulator of PD-L1 transcription, dependent on recruitment by the histone trimethyltransferase SETD2. Next-generation sequencing of MLH1 and MSH6 knockout (KO) cells revealed that MSH6 KO cells have significantly lower microsatellite instability in comparison to MLH1 KO cells, despite MSH6 KO cells having a higher mutational burden. These findings emphasise the need for gene-specific stratification in the MMRd cohort.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101207"},"PeriodicalIF":4.8,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144597485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-08DOI: 10.1016/j.neo.2025.101205
Yujeong Her , Jeong Yeon Kim , Hocheol Shin , Kwangmin Yu , Kyu-Jin Lee , Yi Rang Na , Sangyong Jon , Jung Kyoon Choi , Hyeong-Gon Moon
Recent studies have highlighted the therapeutic potential of targeting tumor neoantigens in solid tumors; however, its efficacy in breast cancer remains unclear. Here, we evaluate the impact of tumor neoantigen-targeted strategies in a syngeneic mouse mammary carcinoma model. Mice previously exposed to 4T1 tumor cells (PETCs) or treated with tumor cell-derived lysates (TdLs) exhibited robust antitumor immunity, leading to reduced tumor growth and metastasis through tumor immune microenvironment remodeling. TdL administration in mice harboring orthotopic tumors significantly enhanced the efficacy of immune checkpoint blockade, suggesting its potential as an immunotherapeutic adjuvant. To further optimize neoantigen-based approaches, we developed a lipid nanoparticle (LNP)-based delivery system for neoantigen peptides, which effectively suppressed tumor progression and metastasis in vivo. Mechanistically, this strategy promoted antigen-specific T cell activation and reshaped the tumor immune landscape, enhancing immune-mediated tumor rejection. These findings underscore the therapeutic promise of personalized tumor neoantigen-targeted immunotherapy in breast cancer and support its further evaluation in clinical settings.
{"title":"Tumor neoantigens as key drivers of significant anti - tumor immunity in triple - negative breast cancer mouse models","authors":"Yujeong Her , Jeong Yeon Kim , Hocheol Shin , Kwangmin Yu , Kyu-Jin Lee , Yi Rang Na , Sangyong Jon , Jung Kyoon Choi , Hyeong-Gon Moon","doi":"10.1016/j.neo.2025.101205","DOIUrl":"10.1016/j.neo.2025.101205","url":null,"abstract":"<div><div>Recent studies have highlighted the therapeutic potential of targeting tumor neoantigens in solid tumors; however, its efficacy in breast cancer remains unclear. Here, we evaluate the impact of tumor neoantigen-targeted strategies in a syngeneic mouse mammary carcinoma model. Mice previously exposed to 4T1 tumor cells (PETCs) or treated with tumor cell-derived lysates (TdLs) exhibited robust antitumor immunity, leading to reduced tumor growth and metastasis through tumor immune microenvironment remodeling. TdL administration in mice harboring orthotopic tumors significantly enhanced the efficacy of immune checkpoint blockade, suggesting its potential as an immunotherapeutic adjuvant. To further optimize neoantigen-based approaches, we developed a lipid nanoparticle (LNP)-based delivery system for neoantigen peptides, which effectively suppressed tumor progression and metastasis in vivo. Mechanistically, this strategy promoted antigen-specific T cell activation and reshaped the tumor immune landscape, enhancing immune-mediated tumor rejection. These findings underscore the therapeutic promise of personalized tumor neoantigen-targeted immunotherapy in breast cancer and support its further evaluation in clinical settings.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101205"},"PeriodicalIF":4.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144572429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Accurate chromosome segregation and ribosomal gene expression silencing are essential for maintaining genome integrity, and disruptions in these processes are key for oncogenesis and cancer progression. Here, we demonstrate a novel role for the transcriptional co-repressor SKI in regulating rDNA and pericentromeric heterochromatin (PCH) silencing in human cells. We found that SKI localizes to the rDNA promoter on acrocentric chromosomes and is crucial for maintaining H3K9 trimethylation (H3K9me3) and repressing 45S rRNA gene expression. SKI is also associated with BSR and HSATII satellites within PCH, where is necessary for H3K9 methylation and recruitment of SUV39H1 and HP1α, key players for heterochromatin silencing and centromere function. Consequently, SKI deficiency disrupted centromere integrity and resulted in aberrant chromosome segregation, micronuclei formation, and chromosome instability. The identification of SKI as a key participant in the epigenetic-mediated silencing of pericentromeric and ribosomal DNA provides a fundamental insight, paving the way for new research into the intricate relationship between transcriptional regulation and genome instability during cancer progression, and opening novel opportunities for therapeutic intervention.
{"title":"SKI regulates rRNA transcription and pericentromeric heterochromatin to ensure centromere integrity and genome stability","authors":"Víctor Pola-Véliz , David Carrero , Eduardo A. Sagredo , Víctor Inostroza , Claudio Cappelli , Solange Rivas , Mirit Bitrán , Evelyn Zambrano , Evelin Gonzalez , Fernanda Morales , Marcia Manterola , Martín Montecino , Ricardo Armisén , Katherine Marcelain","doi":"10.1016/j.neo.2025.101204","DOIUrl":"10.1016/j.neo.2025.101204","url":null,"abstract":"<div><div>Accurate chromosome segregation and ribosomal gene expression silencing are essential for maintaining genome integrity, and disruptions in these processes are key for oncogenesis and cancer progression. Here, we demonstrate a novel role for the transcriptional co-repressor SKI in regulating rDNA and pericentromeric heterochromatin (PCH) silencing in human cells. We found that SKI localizes to the rDNA promoter on acrocentric chromosomes and is crucial for maintaining H3K9 trimethylation (H3K9me3) and repressing 45S rRNA gene expression. SKI is also associated with BSR and HSATII satellites within PCH, where is necessary for H3K9 methylation and recruitment of SUV39H1 and HP1α, key players for heterochromatin silencing and centromere function. Consequently, SKI deficiency disrupted centromere integrity and resulted in aberrant chromosome segregation, micronuclei formation, and chromosome instability. The identification of SKI as a key participant in the epigenetic-mediated silencing of pericentromeric and ribosomal DNA provides a fundamental insight, paving the way for new research into the intricate relationship between transcriptional regulation and genome instability during cancer progression, and opening novel opportunities for therapeutic intervention.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101204"},"PeriodicalIF":4.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144523008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01DOI: 10.1016/j.neo.2025.101203
Shanshan Wang , Weicheng Wu , Zhen Shi , Mei Bin , Fengwei Zhang , Long Cai , Kaiqing Lin , Zhihui Li
Background
Drug resistance prominently hampers the effects of sorafenib in hepatocellular carcinoma (HCC). Epigenetics play important roles in drug resistance. However, the contributions of SET And MYND Domain Containing 2 (SMYD2) to sorafenib resistance in HCC remain unknown. This study is aimed at elucidating the role and mechanism of SMYD2 in sorafenib resistance of HCC.
Methods
Using our well-established sorafenib-resistant hepatocellular carcinoma (HCC) cell lines and xenograft mouse models, we evaluated SMYD2 expression levels. To investigate the biological functions of SMYD2, we conducted a series of functional assays in vitro and in vivo. Transcriptomic profiling via RNA sequencing (RNA-seq) was performed to identify downstream targets of SMYD2. Additionally, chromatin immunoprecipitation (ChIP) assays were employed to elucidate the molecular mechanism. Correlating SMYD2 and target gene expression patterns with clinical outcomes in HCC patients was investigated.
Results
SMYD2 expression was significantly elevated in sorafenib-resistant HCC cells compared with parental cells. Knockdown or overexpression of SMYD2 substantially inhibited or enhanced, respectively, HCC stemness and sorafenib resistance. Mechanistically, SMYD2 promoted BMP4 expression via the maintenance of mono-methylation of histone 3 lysine 4 (H3K4me1) and di-methylation of histone 3 lysine 36 (H3K36me2) modification of its promoter. Meanwhile, knockdown or inhibition of BMP4 suppressed the stemness of sorafenib-resistant cells, inhibited the activation of SMAD1/5/8 (R-SMADs), and decreased the expression of inhibitor Of DNA binding 3 (ID3) gene. Moreover, BMP4 addition or ID3 reconstruction can partly reverse the effect caused by repression of SMYD2 or BMP4. HCC patients with positive co-expression of SMYD2/BMP4 or SMYD2/ID3 or SMYD2/BMP4/ID3 exhibited the worst prognosis.
Conclusions
Our study reveals that SMYD2 is an important epigenetic mediator that activates BMP4/R-SMADs/ID3 axis, leading to enhanced stemness and sorafenib resistance. Thus, SMYD2 might represent a potential biomarker and future epigenetic therapeutic target for sorafenib resistance of HCC.
{"title":"SMYD2 epigenetically activates BMP4/SMAD1/5/8/ID3 axis to enhance cancer stem cell properties and drive sorafenib resistance in hepatocellular carcinoma","authors":"Shanshan Wang , Weicheng Wu , Zhen Shi , Mei Bin , Fengwei Zhang , Long Cai , Kaiqing Lin , Zhihui Li","doi":"10.1016/j.neo.2025.101203","DOIUrl":"10.1016/j.neo.2025.101203","url":null,"abstract":"<div><h3>Background</h3><div>Drug resistance prominently hampers the effects of sorafenib in hepatocellular carcinoma (HCC). Epigenetics play important roles in drug resistance. However, the contributions of SET And MYND Domain Containing 2 (SMYD2) to sorafenib resistance in HCC remain unknown. This study is aimed at elucidating the role and mechanism of SMYD2 in sorafenib resistance of HCC.</div></div><div><h3>Methods</h3><div>Using our well-established sorafenib-resistant hepatocellular carcinoma (HCC) cell lines and xenograft mouse models, we evaluated SMYD2 expression levels. To investigate the biological functions of SMYD2, we conducted a series of functional assays <em>in vitro</em> and <em>in vivo</em>. Transcriptomic profiling via RNA sequencing (RNA-seq) was performed to identify downstream targets of SMYD2. Additionally, chromatin immunoprecipitation (ChIP) assays were employed to elucidate the molecular mechanism. Correlating SMYD2 and target gene expression patterns with clinical outcomes in HCC patients was investigated.</div></div><div><h3>Results</h3><div>SMYD2 expression was significantly elevated in sorafenib-resistant HCC cells compared with parental cells. Knockdown or overexpression of SMYD2 substantially inhibited or enhanced, respectively, HCC stemness and sorafenib resistance. Mechanistically, SMYD2 promoted BMP4 expression via the maintenance of mono-methylation of histone 3 lysine 4 (H3K4me1) and di-methylation of histone 3 lysine 36 (H3K36me2) modification of its promoter. Meanwhile, knockdown or inhibition of BMP4 suppressed the stemness of sorafenib-resistant cells, inhibited the activation of SMAD1/5/8 (R-SMADs), and decreased the expression of <em>inhibitor Of DNA binding 3 (ID3)</em> gene. Moreover, BMP4 addition or ID3 reconstruction can partly reverse the effect caused by repression of SMYD2 or BMP4. HCC patients with positive co-expression of SMYD2/BMP4 or SMYD2/ID3 or SMYD2/BMP4/ID3 exhibited the worst prognosis.</div></div><div><h3>Conclusions</h3><div>Our study reveals that SMYD2 is an important epigenetic mediator that activates BMP4/R-SMADs/ID3 axis, leading to enhanced stemness and sorafenib resistance. Thus, SMYD2 might represent a potential biomarker and future epigenetic therapeutic target for sorafenib resistance of HCC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101203"},"PeriodicalIF":4.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144522808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01DOI: 10.1016/j.neo.2025.101206
RuiXin Zheng , YuXiao Li , KaiXin Shi , YuanYuan Pan , KaiYi Liu , JinCheng Song , Li Li
B-cell lymphoma, a malignancy in hematology with high heterogeneity, has its genesis and progression intricately associated with immune system regulation. Over the past three decades, transformative breakthroughs in B-cell malignancy investigations have emerged through paradigm-shifting molecular discoveries. Nevertheless, numerous hurdles persist in attaining a comprehensive understanding and effective treatment of this disease. Novel chemotherapeutic strategies demonstrate promising potential in B-cell lymphoma management, particularly through targeting immune checkpoints such as PD-1 (Programmed Cell Death Protein 1), LAG-3 (Lymphocyte-activation Gene 3), TIM-3 (T-cell Immunoglobulin and Mucin-domain containing-3), and TIGIT (T-cell Immunoreceptor with Ig and ITIM Domains) play pivotal regulatory roles within the immune system. These molecules critically orchestrate immune cell activation dynamics, proliferative capacity, and effector functions, thereby preserving immunological homeostasis. Deciphering the functional architecture of co-inhibitory checkpoints (e.g., PD-1/CTLA-4) in lymphomagenesis serves dual imperatives: deconstructing tumor immune evasion programs while establishing conceptual frameworks for precision immunotherapeutics development. PD-1 engagement with PD-L1/PD-L2 impairs T lymphocyte activation, facilitating tumor immune evasion. Deciphering these molecular processes enables therapeutic agents to employ targeted blockade strategies to restore antitumor immunity in lymphomas. Moreover, in-depth research on these checkpoints holds great promise for the discovery of novel biomarkers. These biomarkers may help predict responses to immunotherapy in lymphoma patients. This would enable clinicians to tailor personalized treatment plans for each patient, maximizing the therapeutic efficacy while minimizing unnecessary side-effects. Certain genetic signatures related to these immune checkpoints might be identified as predictors of a favorable response to PD-1 inhibitor-based immunotherapy. This analysis systematically deciphers the molecular interplay of PD-1/LAG-3/TIM-3/TIGIT immune checkpoint axes, delineating their regulatory dynamics in B-cell lymphomagenesis. It systematically summarizes the current research achievements, delves into the existing problems, and explores the future research directions. This approach seeks to advance dual contributions to fundamental science and clinical application in B-cell lymphoma immunotherapy, thereby facilitating therapeutic innovations while deepening mechanistic comprehension of disease pathogenesis. By doing so, it aims to provide valuable insights for both basic research and clinical translation in the field of B-cell lymphoma immunotherapy, ultimately enabling advancements in patient care and deeper insights into this multifaceted condition.
{"title":"New horizons in B-cell lymphoma immunotherapy: From immune checkpoints to precision medicine","authors":"RuiXin Zheng , YuXiao Li , KaiXin Shi , YuanYuan Pan , KaiYi Liu , JinCheng Song , Li Li","doi":"10.1016/j.neo.2025.101206","DOIUrl":"10.1016/j.neo.2025.101206","url":null,"abstract":"<div><div>B-cell lymphoma, a malignancy in hematology with high heterogeneity, has its genesis and progression intricately associated with immune system regulation. Over the past three decades, transformative breakthroughs in B-cell malignancy investigations have emerged through paradigm-shifting molecular discoveries. Nevertheless, numerous hurdles persist in attaining a comprehensive understanding and effective treatment of this disease. Novel chemotherapeutic strategies demonstrate promising potential in B-cell lymphoma management, particularly through targeting immune checkpoints such as PD-1 (Programmed Cell Death Protein 1), LAG-3 (Lymphocyte-activation Gene 3), TIM-3 (T-cell Immunoglobulin and Mucin-domain containing-3), and TIGIT (T-cell Immunoreceptor with Ig and ITIM Domains) play pivotal regulatory roles within the immune system. These molecules critically orchestrate immune cell activation dynamics, proliferative capacity, and effector functions, thereby preserving immunological homeostasis. Deciphering the functional architecture of co-inhibitory checkpoints (e.g., PD-1/CTLA-4) in lymphomagenesis serves dual imperatives: deconstructing tumor immune evasion programs while establishing conceptual frameworks for precision immunotherapeutics development. PD-1 engagement with PD-L1/PD-L2 impairs T lymphocyte activation, facilitating tumor immune evasion. Deciphering these molecular processes enables therapeutic agents to employ targeted blockade strategies to restore antitumor immunity in lymphomas. Moreover, in-depth research on these checkpoints holds great promise for the discovery of novel biomarkers. These biomarkers may help predict responses to immunotherapy in lymphoma patients. This would enable clinicians to tailor personalized treatment plans for each patient, maximizing the therapeutic efficacy while minimizing unnecessary side-effects. Certain genetic signatures related to these immune checkpoints might be identified as predictors of a favorable response to PD-1 inhibitor-based immunotherapy. This analysis systematically deciphers the molecular interplay of PD-1/LAG-3/TIM-3/TIGIT immune checkpoint axes, delineating their regulatory dynamics in B-cell lymphomagenesis. It systematically summarizes the current research achievements, delves into the existing problems, and explores the future research directions. This approach seeks to advance dual contributions to fundamental science and clinical application in B-cell lymphoma immunotherapy, thereby facilitating therapeutic innovations while deepening mechanistic comprehension of disease pathogenesis. By doing so, it aims to provide valuable insights for both basic research and clinical translation in the field of B-cell lymphoma immunotherapy, ultimately enabling advancements in patient care and deeper insights into this multifaceted condition.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101206"},"PeriodicalIF":4.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144518183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-30DOI: 10.1016/j.neo.2025.101196
Alexander Lubosch , Lauren Pitt , Caren Zoeller , Franziska Wirth , Tarik Exner , Barbara Steigenberger , Guido Wabnitz , Jutta Schroeder-Braunstein , Inaam A. Nakchbandi
Cancer-associated fibroblasts remain poorly understood, with some of them originating from the bone marrow. We therefore took advantage of the diversity of bone marrow stromal cells to shed light on how fibroblasts modulate cancer growth.
In two murine cancer models, adding these fibroblasts to tumor cells resulted in smaller lesions. Suppression was enhanced by pretreatment with fibronectin, while genetic deletion of fibronectin in a small subpopulation of stromal cells expressing osterix/sp7 restored growth. The suppressive stromal population showed two more characteristics: the absence of CD31/pecam1 and CD105/endoglin. However, only a decrease in CD105/ENDOGLIN in melanoma patients translated in improved survival. Mechanistically, fibronectin or fibronectin fragments activate integrin α5β1 and TLR4 and increase chemokine production by stromal cells ultimately leading to enhanced recruitment and activity of Ly6G+ myeloid cells without T-cell involvement.
This work thus characterizes a beneficial interaction between stromal cells and neutrophils enhancing the immune response against early cancer.
{"title":"The immune response against cancer is modulated by stromal cell fibronectin","authors":"Alexander Lubosch , Lauren Pitt , Caren Zoeller , Franziska Wirth , Tarik Exner , Barbara Steigenberger , Guido Wabnitz , Jutta Schroeder-Braunstein , Inaam A. Nakchbandi","doi":"10.1016/j.neo.2025.101196","DOIUrl":"10.1016/j.neo.2025.101196","url":null,"abstract":"<div><div>Cancer-associated fibroblasts remain poorly understood, with some of them originating from the bone marrow. We therefore took advantage of the diversity of bone marrow stromal cells to shed light on how fibroblasts modulate cancer growth.</div><div>In two murine cancer models, adding these fibroblasts to tumor cells resulted in smaller lesions. Suppression was enhanced by pretreatment with fibronectin, while genetic deletion of fibronectin in a small subpopulation of stromal cells expressing osterix/<em>sp7</em> restored growth. The suppressive stromal population showed two more characteristics: the absence of CD31/<em>pecam1</em> and CD105/<em>endoglin</em>. However, only a decrease in CD105/<em>ENDOGLIN</em> in melanoma patients translated in improved survival. Mechanistically, fibronectin or fibronectin fragments activate integrin α5β1 and TLR4 and increase chemokine production by stromal cells ultimately leading to enhanced recruitment and activity of Ly6G<sup>+</sup> myeloid cells without T-cell involvement.</div><div>This work thus characterizes a beneficial interaction between stromal cells and neutrophils enhancing the immune response against early cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101196"},"PeriodicalIF":4.8,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-30DOI: 10.1016/j.neo.2025.101198
Chunli Zhang , Limin Huang , Zeyu Li , Qian Wang , Nanbin Liu , Chongyu Zhang , Xi Liu , Chen Zhang , Gaixia He , Jin Sun , Zongfang Li , Hongwei Tian
Tumors often evade immune surveillance by crippling their immunogenicity in the microenvironment. DHX34, an RNA helicase involved in nonsense-mediated mRNA decay pathway, is critical for aberrant RNA degradation. However, the effect of DHX34 in regulating the immunogenicity in hepatocellular carcinoma (HCC) is still unclear. Here, a surprising function of DHX34 in inhibited HCC immunogenicity is identified. DHX34-deficient tumors were infiltrated by activated T cells that impaired tumor growth and enhanced survival in mice. Mechanistically, DHX34 depletion triggered dsRNA accumulation which may activate cytosolic RNA-sensing pathway effectors such as MAVS, p-IKK, p-IRF3, and the subsequent type-I interferon response, evoking tumor-intrinsic immunity and leading to CD8 T activation. Collectively, DHX34 is implicated as a regulator that orchestrates a barrier in HCC by suppressing dsRNA-driven innate immune activation. Targeting DHX34 may enhance tumor immunogenicity and synergize with immunotherapies, offering a novel therapeutic strategy for HCC.
{"title":"DHX34 deficiency triggers tumor-intrinsic immunity via a dsRNA-mediated type I interferon pathway activation in HCC","authors":"Chunli Zhang , Limin Huang , Zeyu Li , Qian Wang , Nanbin Liu , Chongyu Zhang , Xi Liu , Chen Zhang , Gaixia He , Jin Sun , Zongfang Li , Hongwei Tian","doi":"10.1016/j.neo.2025.101198","DOIUrl":"10.1016/j.neo.2025.101198","url":null,"abstract":"<div><div>Tumors often evade immune surveillance by crippling their immunogenicity in the microenvironment. DHX34, an RNA helicase involved in nonsense-mediated mRNA decay pathway, is critical for aberrant RNA degradation. However, the effect of DHX34 in regulating the immunogenicity in hepatocellular carcinoma (HCC) is still unclear. Here, a surprising function of DHX34 in inhibited HCC immunogenicity is identified. DHX34-deficient tumors were infiltrated by activated T cells that impaired tumor growth and enhanced survival in mice. Mechanistically, DHX34 depletion triggered dsRNA accumulation which may activate cytosolic RNA-sensing pathway effectors such as <em>MAVS, p-IKK, p-IRF3</em>, and the subsequent type-I interferon response, evoking tumor-intrinsic immunity and leading to CD8 T activation. Collectively, DHX34 is implicated as a regulator that orchestrates a barrier in HCC by suppressing dsRNA-driven innate immune activation. Targeting DHX34 may enhance tumor immunogenicity and synergize with immunotherapies, offering a novel therapeutic strategy for HCC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101198"},"PeriodicalIF":4.8,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144518129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-24DOI: 10.1016/j.neo.2025.101202
Matjaz Rokavec , Heiko Hermeking
miRTARGET (https://www.mirtarget.com) is a web tool for the identification of miRNA targets. It integrates experimental miRNA-related datasets and computational algorithms to generate prediction scores for targets of 1744 human miRNAs. The score is based on four dataset categories: mRNA profiling in cells or mice after (1) ectopic miRNA expression or (2) miRNA inactivation by knock-out or knock-down, (3) correlation analyses of mRNA and miRNA expression profiles, and (4) ten computational miRNA target prediction algorithms. Our validation analyses demonstrated a significant enrichment of published/validated miRNA targets among the predicted miRNA targets, underlining the reliability of the miRTARGET prediction score. In addition, miRTARGET integrates cancer-related datasets from primary tumors and cell lines, allowing users to filter/extract miRNA targets based on cancer cell line dependency, survival associations, and differential expression between tumor and normal tissues across 32 cancer entities. As a proof-of-concept, miRTARGET identified CDC7 and its regulatory unit DBF4 as the top cancer-associated predicted targets of the tumor suppressive miRNA miR-30a. Therefore, the CDC7-DBF4 complex may represent an attractive candidate therapeutic target for the treatment of cancers with miR-30a inactivation. Altogether, miRTARGET is a powerful and user-friendly web tool for exploring miRNA targets with therapeutic or prognostic potential in cancer.
{"title":"miRTARGET: An integrated web tool for the identification of microRNA targets with potential therapeutic or prognostic value in cancer","authors":"Matjaz Rokavec , Heiko Hermeking","doi":"10.1016/j.neo.2025.101202","DOIUrl":"10.1016/j.neo.2025.101202","url":null,"abstract":"<div><div>miRTARGET (<span><span>https://www.mirtarget.com</span><svg><path></path></svg></span>) is a web tool for the identification of miRNA targets. It integrates experimental miRNA-related datasets and computational algorithms to generate prediction scores for targets of 1744 human miRNAs. The score is based on four dataset categories: mRNA profiling in cells or mice after (1) ectopic miRNA expression or (2) miRNA inactivation by knock-out or knock-down, (3) correlation analyses of mRNA and miRNA expression profiles, and (4) ten computational miRNA target prediction algorithms. Our validation analyses demonstrated a significant enrichment of published/validated miRNA targets among the predicted miRNA targets, underlining the reliability of the miRTARGET prediction score. In addition, miRTARGET integrates cancer-related datasets from primary tumors and cell lines, allowing users to filter/extract miRNA targets based on cancer cell line dependency, survival associations, and differential expression between tumor and normal tissues across 32 cancer entities. As a proof-of-concept, miRTARGET identified <em>CDC7</em> and its regulatory unit <em>DBF4</em> as the top cancer-associated predicted targets of the tumor suppressive miRNA miR-30a. Therefore, the CDC7-DBF4 complex may represent an attractive candidate therapeutic target for the treatment of cancers with miR-30a inactivation. Altogether, miRTARGET is a powerful and user-friendly web tool for exploring miRNA targets with therapeutic or prognostic potential in cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101202"},"PeriodicalIF":4.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144366119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-23DOI: 10.1016/j.neo.2025.101200
Mingshuang Wang , Liwei Pang , Yingjie Sun , Jingjing Han , Jiani Fan , Wenhui Shen , Xiaonan Hu , Bingqian Yang , Haoming Ning , Yanan Kong , Duo Li , Wenshan Zhao , Ranran Shi , Ling Ran , Yuanming Qi , Yahong Wu
Endocrine therapy has shown significant clinical efficacy in estrogen receptor alpha (ERα)-positive breast cancer management, but the emergence of therapy-resistant mutations significantly undermines treatment outcomes, frequently leading to disease progression and metastasis. Among these resistance mechanisms, mutations in the ESR1 gene are particularly prevalent, detectable in 76% of endocrine therapy-resistant tumor specimens. The identification of immunogenic neoepitopes derived from mutant ESR1 offers a promising therapeutic avenue for patients with endocrine therapy-resistant breast cancer. In this study, we systematically investigated the mutational landscape of ESR1 across various cancer types, with particular emphasis on mutation frequency and spectrum analysis. Our findings revealed that non-synonymous ESR1 mutations predominantly occurred in breast cancer, clustering at four distinct hotspot sites: K303, E380, Y537 and D538. We further characterized the mutation prevalence at these hotspots across different breast cancer subtypes. Through comprehensive screening, we identified eight human leukocyte antigen (HLA)-A*0201 restricted immunogenic neoepitopes derived from ESR1 hotspot mutations. These neoepitopes demonstrated the capacity to elicit specific cytotoxic T lymphocytes (CTLs) responses both in vitro and in vivo. The induced CTLs exhibited specific recognition and cytotoxic activity against both T2A2 cells loaded with mutant neoepitopes and HLA-A*0201-positive breast cancer cells transfected with minigene encoding mutant neoepitopes. Notably, adoptive transfer of T cells primed with a peptide pool containing these eight neoepitopes significantly suppressed tumor growth and enhanced CD8+ T cells infiltration within tumor tissue. These findings suggest that the identified neoepitopes represent promising candidates for the development of tumor shared neoantigen vaccines.
{"title":"Screening and identification of HLA-A2-restricted neoepitopes for immunotherapy in endocrine therapy-resistant breast cancer","authors":"Mingshuang Wang , Liwei Pang , Yingjie Sun , Jingjing Han , Jiani Fan , Wenhui Shen , Xiaonan Hu , Bingqian Yang , Haoming Ning , Yanan Kong , Duo Li , Wenshan Zhao , Ranran Shi , Ling Ran , Yuanming Qi , Yahong Wu","doi":"10.1016/j.neo.2025.101200","DOIUrl":"10.1016/j.neo.2025.101200","url":null,"abstract":"<div><div>Endocrine therapy has shown significant clinical efficacy in estrogen receptor alpha (ERα)-positive breast cancer management, but the emergence of therapy-resistant mutations significantly undermines treatment outcomes, frequently leading to disease progression and metastasis. Among these resistance mechanisms, mutations in the ESR1 gene are particularly prevalent, detectable in 76% of endocrine therapy-resistant tumor specimens. The identification of immunogenic neoepitopes derived from mutant ESR1 offers a promising therapeutic avenue for patients with endocrine therapy-resistant breast cancer. In this study, we systematically investigated the mutational landscape of ESR1 across various cancer types, with particular emphasis on mutation frequency and spectrum analysis. Our findings revealed that non-synonymous ESR1 mutations predominantly occurred in breast cancer, clustering at four distinct hotspot sites: K303, E380, Y537 and D538. We further characterized the mutation prevalence at these hotspots across different breast cancer subtypes. Through comprehensive screening, we identified eight human leukocyte antigen (HLA)-A*0201 restricted immunogenic neoepitopes derived from ESR1 hotspot mutations. These neoepitopes demonstrated the capacity to elicit specific cytotoxic T lymphocytes (CTLs) responses both <em>in vitro</em> and <em>in vivo</em>. The induced CTLs exhibited specific recognition and cytotoxic activity against both T2A2 cells loaded with mutant neoepitopes and HLA-A*0201-positive breast cancer cells transfected with minigene encoding mutant neoepitopes. Notably, adoptive transfer of T cells primed with a peptide pool containing these eight neoepitopes significantly suppressed tumor growth and enhanced CD8<sup>+</sup> T cells infiltration within tumor tissue. These findings suggest that the identified neoepitopes represent promising candidates for the development of tumor shared neoantigen vaccines.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101200"},"PeriodicalIF":4.8,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144338697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-23DOI: 10.1016/j.neo.2025.101199
Yufei Wang , Yuanlin Sun , Weizhu Zhao , Jiazi Zhang , Xiaofeng Wang , Fangqi Hu , Zhifei Han , Longgang Wang , Luguang Liu , Bing Liu , Liqing Liu , Bo Bi , Dong Sun , Bingtian Liu , Jie Chai
Although aberrant activation of the Hippo/YAP axis has been implicated in the development of gastric cancer, functional studies of this cascade in the context of gastric signet-ring cell carcinoma (GSRC) remain absent. Our previous single-cell sequencing results showed that G protein-coupled estrogen receptor (GPER) is overexpressed in GSRC, and this overexpression is associated with aberrant activation of the Hippo/YAP axis. In this study, we integrated in vitro cytological functional assays with GSRC cell lines and in vivo xenograft nude mice models to elucidate the functional implications of GPER in GSRC. The overexpression of GPER was identified as being associated with more unfavorable outcomes in GSRC. Its activation facilitated tumor proliferation by YAP nuclear translocation and subsequent transcriptional activation. Mechanistically, GPER inhibited LATS1-mediated YAP phosphorylation by competitively binding to ARRB2, thereby enhancing YAP activity. Moreover, YAP was shown to bind to the GPER promoter, forming a positive feedback loop that reinforced oncogenic signaling. Pharmacological inhibition of GPER using G-15 reduced YAP activation and effectively attenuated tumor aggressiveness, highlighting the GPER-YAP feedback loop as a potential therapeutic target for GSRC. This study underscores the pivotal role of the GPER-YAP positive feedback loop in GSRC and proposes dual inhibition of GPER and YAP as a promising therapeutic strategy for GSRC.
{"title":"Regulatory mechanisms of the Hippo/YAP axis by G-protein coupled estrogen receptor in gastric signet-ring cell carcinoma","authors":"Yufei Wang , Yuanlin Sun , Weizhu Zhao , Jiazi Zhang , Xiaofeng Wang , Fangqi Hu , Zhifei Han , Longgang Wang , Luguang Liu , Bing Liu , Liqing Liu , Bo Bi , Dong Sun , Bingtian Liu , Jie Chai","doi":"10.1016/j.neo.2025.101199","DOIUrl":"10.1016/j.neo.2025.101199","url":null,"abstract":"<div><div>Although aberrant activation of the Hippo/YAP axis has been implicated in the development of gastric cancer, functional studies of this cascade in the context of gastric signet-ring cell carcinoma (GSRC) remain absent. Our previous single-cell sequencing results showed that G protein-coupled estrogen receptor (GPER) is overexpressed in GSRC, and this overexpression is associated with aberrant activation of the Hippo/YAP axis. In this study, we integrated <em>in vitro</em> cytological functional assays with GSRC cell lines and <em>in vivo</em> xenograft nude mice models to elucidate the functional implications of GPER in GSRC. The overexpression of GPER was identified as being associated with more unfavorable outcomes in GSRC. Its activation facilitated tumor proliferation by YAP nuclear translocation and subsequent transcriptional activation. Mechanistically, GPER inhibited LATS1-mediated YAP phosphorylation by competitively binding to ARRB2, thereby enhancing YAP activity. Moreover, YAP was shown to bind to the GPER promoter, forming a positive feedback loop that reinforced oncogenic signaling. Pharmacological inhibition of GPER using G-15 reduced YAP activation and effectively attenuated tumor aggressiveness, highlighting the GPER-YAP feedback loop as a potential therapeutic target for GSRC. This study underscores the pivotal role of the GPER-YAP positive feedback loop in GSRC and proposes dual inhibition of GPER and YAP as a promising therapeutic strategy for GSRC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"67 ","pages":"Article 101199"},"PeriodicalIF":4.8,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144366118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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