Oncogene最新文献

{"title":"The RPS15-DDX21 complex drives prostate malignancy through transcriptional activation of SCD1.","authors":"Yuning Liao, Wenshuang Sun, Yuting Li, Yuanfei Deng, Qing Liu, Shusha Yin, Yujie Xiang, E-Ying Peng, Yu Yao, Wanying He, Zhenlong Shao, Gengxi Cai, Hongbiao Huang","doi":"10.1038/s41388-026-03818-5","DOIUrl":"https://doi.org/10.1038/s41388-026-03818-5","url":null,"abstract":"<p><p>Development of castration resistance and distant metastasis remain two major clinical challenges in prostate cancer (PCa) treatment. By analyzing multiple public cancer datasets, we found that ribosomal protein S15 (RPS15) is overexpressed in PCa and related to its metastasis. Beyond its canonical role as a structural component of the ribosome, emerging evidence has highlighted the extraribosomal functions of RPS15 in disease progression. Our study demonstrates that RPS15 significantly promotes proliferation and migration in PCa through the establishment of RPS15 knockdown cells and xenograft models. Mechanistically, RPS15 interacts with the functional domain of DExD-box helicase 21 (DDX21) and facilitates the binding of DDX21 to the transcription start region of stearoyl-CoA desaturase-1 (SCD1), thereby enhancing its transcriptional activity and protein expression to drive the growth, ferroptosis-resistance, and metastasis of PCa cells. Moreover, analysis of clinical samples revealed that RPS15, DDX21, and SCD1 are concomitantly upregulated and exhibit strong positive correlations in PCa tissues. Collectively, our findings uncover the significance of the RPS15-DDX21-SCD1 axis in PCa development, expanding the understanding of noncanonical functions of ribosomal proteins and providing new insights for PCa management.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SNRPD2-CPSF7-UBE2K axis drives ovarian cancer progression via alternative splicing-polyadenylation crosstalk.","authors":"Yingwei Li, Zhongshao Chen, Yuchao Diao, Qianqian Gao, Yuehan Gao, Yingying Pu, Ning Yang","doi":"10.1038/s41388-026-03812-x","DOIUrl":"https://doi.org/10.1038/s41388-026-03812-x","url":null,"abstract":"<p><p>Aberrant alternative polyadenylation (APA) and alternative splicing (AS) contribute to numerous diseases, including cancer; however, their coordinated roles in ovarian cancer remain poorly understood. Here, we investigated CPSF7, an APA factor markedly upregulated in ovarian cancer and associated with poor prognosis. Silencing CPSF7 suppressed proliferation, migration, and invasion of ovarian cancer cells, while antisense oligonucleotides (ASOs) targeting CPSF7 reduced tumor growth in a patient‑derived xenograft (PDX) model. Mechanistically, knockdown of the splicing factor SNRPD2 induced exon 4 skipping in CPSF7 pre‑mRNA. Loss of exon 4 disrupted the RNA recognition motif (RRM) domain essential for CPSF7‑mediated pre‑mRNA cleavage and polyadenylation, and introduced premature termination codons (PTCs) that generated noncoding transcripts subject to nonsense‑mediated decay (NMD), thereby reducing CPSF7 expression. Thus, efficient splicing mediated by SNRPD2 is crucial for sustaining high CPSF7 levels in ovarian cancer cells. Functional assays showed that CPSF7 knockdown reduced proliferation and metastatic potential in cells with elevated SNRPD2, suggesting that CPSF7 is a key mediator of SNRPD2-driven oncogenesis. Moreover, CPSF7 governed specific APA events to maintain transcript stability, with UBE2K identified as a critical downstream target. CPSF7 preferentially bound distal polyadenylation signals (PASs) within the predominant UBE2K transcript (UBE2K-201), thereby increasing its mRNA stability and maintaining high functional UBE2K expression. Collectively, these findings reveal that AS and APA are interconnected in ovarian cancer via the SNRPD2-CPSF7-UBE2K axis, which drives disease progression and represents a promising target for therapeutic intervention.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147841167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PinX1 inhibits migrasomes-mediated mitochondrial transfer to confer cisplatin sensitivity in nasopharyngeal carcinoma.","authors":"Juan Zhang, Junqi Wang, Tingfeng Liang, Fang Chen, Zhenchao Zhu, Yong He, Xueyong Hu, Jing Li, Shuaijun Chen, Chaosheng Yu","doi":"10.1038/s41388-026-03741-9","DOIUrl":"https://doi.org/10.1038/s41388-026-03741-9","url":null,"abstract":"<p><p>Chemotherapy resistance is a major factor contributing to the failure of nasopharyngeal carcinoma (NPC) treatment. Migrasomes can export damaged mitochondria out of the cell, and the timely removal of damaged mitochondria is key to cancer cell resistance. However, whether migrasomes regulate tumor resistance remains unknown. Here, we elucidated the role and mechanism of migrasomes in chemoresistance of NPC. We found that the formation of migrasomes was increased in cisplatin-resistant NPC cells, and inhibiting migrasome formation reduced cisplatin resistance. PinX1 was lowly expressed in tumor tissues of patients with high migrasome scores. Upstream mechanism analyses showed that TP53 was effectively bound to the promoter of PinX1, thereby enhancing its transcriptional activity. Knockdown of PinX1 facilitated migrasome formation via its telomerase inhibitory domain 252-328aa region binding to Rab11a, which relied on serine residues at the N-terminal 25aa site for promoting migrasome formation. Mechanistically, PinX1 recruited RanBP2 to induce the SUMOylation of Rab11a, leading to the degradation of Rab11a at the K207 site. Furthermore, PinX1 reduced cancer cell energy metabolism by inhibiting the export of damaged mitochondria via migrasomes. Collectively, TP53-activated PinX1 recruits RanBP2 to Rab11a, triggering Rab11a K207 SUMOylation and degradation, leading to impaired migrasome formation and mitochondrial transfer, and ultimately suppresses cisplatin resistance in NPC. Our study provides a new target for clinical reversal of chemotherapy resistance in patients with NPC.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147841179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular insights into DDX3X-androgen receptor mRNA regulation via non-canonical G-quadruplex in castration-resistant prostate cancer.","authors":"Han Zhang, Teresa T Liu, Feixuan Wu, Avan N Colah, Emily A Ricke, Lingjun Li, Andrea A Putnam, William A Ricke","doi":"10.1038/s41388-026-03777-x","DOIUrl":"https://doi.org/10.1038/s41388-026-03777-x","url":null,"abstract":"<p><p>Prostate cancer (PC) is one of the most common malignancies in men, and the emergence of androgen receptor-low/negative castration-resistant PC (ARL/- CRPC) following androgen receptor signaling inhibitor (ARSI) therapy remains a critical clinical challenge. The RNA-binding protein DEAD-box helicase 3 X-linked (DDX3X) has been implicated in the translational regulation of androgen receptor (AR) mRNA; however, the underlying binding mechanisms are not well defined. Here, we show that DDX3X colocalizes with AR mRNA in ARL/- CRPC cells and selectively recognizes non-canonical RNA G-quadruplex (rG4) motifs within the sequence of AR mRNA. RNA immunoprecipitation sequencing (RIP-seq) revealed enrichment of DDX3X-AR mRNA interactions in ARL/- CRPC cells. Fluorescence imaging confirmed the colocalization of DDX3X and AR mRNA within cytoplasmic granules, and biochemical assays confirmed the ability of selected AR mRNA fragments to form rG4 structures bound by DDX3X. Proteomic profiling of DDX3X-Ras GTPase-activating protein-binding protein 1 (G3BP1) complexes identified several RNA-binding proteins, including IGF2BP1, PUM2, and UBAP2, which may act as candidate cofactors. Together, these findings shed light on the interaction between AR mRNA and DDX3X and identify putative protein partners, offering insights into future therapeutic strategies.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147841192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Olfactomedin 4 orchestrates TGF-β/CEACAM6 axis, promoting cell-autonomous epithelial to mesenchymal transition during gallbladder epithelium carcinogenesis.","authors":"Songlin Yang, Wenwen Huang, Qingju Zeng, Xiaodan Wang, Shucheng Lin, Mingyao Meng, Liqiong Wang, Hui Wang, Ruotian Wang, Lin Li, Xiaofang Chen, Zichun Wei, Zhuying Lin, Qiuwen Ye, Ruhong Li, Jing Tan, Wenju Wang","doi":"10.1038/s41388-026-03808-7","DOIUrl":"https://doi.org/10.1038/s41388-026-03808-7","url":null,"abstract":"<p><p>Gallbladder cancer (GBC) is a highly lethal disease which is usually diagnosed at advanced stage owing to unavailable screening tools and effective therapies. Persistent inflammation induced by various risk factors is the main cause of GBC, however, the molecular program remains elusive. Unveiling the molecular trajectory and events during gallbladder epithelium malignant transformation contribute to prevention and drug discovery for GBC. Single cell RNA sequencing was performed by using 4 gallbladder adenoma and cancer samples. Pseudotime trajectory analyses were employed to reconstruct epithelium transformation track in order to identify crucial genes which promoted GBC development. Functional and mechanism studies were performed to validate the regulatory network and cell behavior in vitro and in vivo. Three clusters of gallbladder epithelium were identified among GBC microenvironment which were characterized by distinct epithelial mesenchymal transition (EMT) and inflammation states. Cell adhesion molecular binding was the most significant GO term between EMT high and low states, in which OLFM4 was differentially expressed gene participated. Further studies implicated that OLFM4 could promote GBC metastasis and activate EMT through CEACAM6/AKT signaling cascade, and the CEACAM6 expression was regulated by TGF-β/Smad3 pathway. Interestingly, we disclosed that TGFβR1 was the functional receptor of OLFM4, through which the tumorigenic signaling of OLFM4 was transduced. These findings suggest the oncogenic role of OLFM4 during GBC carcinogenesis which can be a candidate biomarker of GBC, and OLFM4, TGFβR1 and downstream signaling elements are promising therapeutic targets for GBC.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147778048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crosstalk between integrin signaling and NAD⁺ biosynthetic pathways promotes glycolysis, proliferation, survival, and tumor growth in triple-negative breast cancer.","authors":"Orion Spellecy, Javeria Qadir, Rongbo Han, Kai Zhu, Bingwei Xu, Yang Zhang, Isha Aryal, Ruei-Lung Lin, An-Hsuan Lin, Abu Saleh Mosa Faisal, Dana Napier, Dava Piecoro, Tim Scott, Penghui Lin, Li Chen, Lawrence D Brewer, Chi Wang, Natasha Kyprianou, Zhenheng Guo, Ruihua Guo, Olivier Thibault, Burton B Yang, Xiuwei H Yang","doi":"10.1038/s41388-026-03780-2","DOIUrl":"https://doi.org/10.1038/s41388-026-03780-2","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited therapeutic options. Here, we investigated how integrin-dependent signaling pathways regulate tumor metabolism and therapeutic vulnerability in TNBC. Pharmacological inhibition of the integrin/FAK axis and/or BRD4 induced cell cycle arrest, autophagy, and senescence in highly proliferative cells, consistent with a metabolic stress phenotype. Metabolomic analyses using [U-¹³C]-glucose revealed a marked suppression of glycolytic carbon flux, accompanied by an approximately 30-47% reduction in intracellular NAD⁺ levels and coordinated alterations in NADH and tricarboxylic acid (TCA) cycle intermediate α-ketoglutarate. Mechanistically, we identified nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD⁺ biosynthesis, as a central metabolic node integrating signaling/function of the two axes. NAMPT expression/activity was sustained transcriptionally or post-translationally, including sirtuin-associated deacetylation and neddylation-dependent proteasomal turnover. In BRCA1/2-deficient TNBC, integrin-FAK and NAMPT/NAD⁺ pathways converged on Wnt/β-catenin signaling to regulate DNA repair, and response to PARP1/2 inhibitors. Co-inhibiting FAK and NAMPT synergistically suppressed tumor growth by approximately 80%. Elevated stromal NAMPT expression was associated with a trend toward favorable clinical outcomes. Collectively, these findings uncover a previously unrecognized crosstalk between integrin/FAK and NAMPT/NAD⁺ pathways in TNBC and identify a synthetic lethal-like therapeutic vulnerability that warrants further evaluation in clinically relevant models.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KDM4B/DHX9 promotes chemoresistance in small-cell lung cancer through the MYCN-driven signaling pathway.","authors":"Qiong Lyu, Huiying Liu, Weitao Shen, Zhihong Lin, Yueming Zhang, Haoxuan Ying, Qianshan Long, Xiang Cao, Jian Zhang, Jian Shi, Zhengang Qiu","doi":"10.1038/s41388-026-03798-6","DOIUrl":"https://doi.org/10.1038/s41388-026-03798-6","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) is prone to developing chemoresistance, which is associated with epigenetic reprogramming. While LSD1-mediated histone demethylation has been reported, a systematic investigation into the role of histone demethylases in SCLC chemoresistance is lacking. In this study, we established nine chemoresistant cell lines from parental cells via gradual dose escalation and conducted RNA sequencing, followed by linear regression and random effects meta-analysis to identify genes associated with chemoresistance among 23 histone demethylases. We subsequently validated our findings using two neuroendocrine SCLC cell lines and their corresponding chemoresistant counterparts. We identified KDM4B as a key driver of chemoresistance, with immunohistochemical analysis revealing its elevated expression in chemoresistant tissues from SCLC patients, although its association with neuroendocrine subtypes warrants further investigation. KDM4B promoted chemoresistance through the Hedgehog pathway by enhancing cell proliferation and stemness. Mechanistically, KDM4B interacts with DHX9 and corecruits to the MYCN promoter to promote its transcription and activate the Hedgehog signaling pathway. An inhibitor of DHX9 had synergistic antitumor effects with cisplatin and etoposide, and effectively rescued the chemosensitivity of SCLC both in vitro and in vivo. These findings provide valuable insights for future studies aimed at developing therapeutic strategies to overcome chemoresistance in SCLC.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MS4A4A promotes macrophages M2 polarization via NF-κB /JAK-STAT6 axis, resulting GBM malignant progression.","authors":"Ziwei Li, Chunfa Wu, Zhongliang Cui, Bo Liang, Chen Wang, Mingchen Yu, Yishuo Sun, Di Wang, You Zhai, Changqing Pan, Jiazheng Zhang, Zhongfang Shi, Tao Jiang, Wei Zhang","doi":"10.1038/s41388-026-03773-1","DOIUrl":"https://doi.org/10.1038/s41388-026-03773-1","url":null,"abstract":"<p><p>The immunosuppressive tumor microenvironment (TME) is a major issue in the malignant progression of glioma patients. The membrane spanning four domains A4A (MS4A4A) has a relationship with M2 polarization of macrophages, and participates in the malignant progression of various cancers. Therefore, exploration of the key role of MS4A4A contributing to glioma biological processes is urgently needed. We performed the bioinformatics analysis of M2 gene expression and built a model predicting the prognosis of glioma patients. Knocking down or overexpressing MS4A4A was achieved in macrophages, and we identified the polarization of macrophages with different MS4A4A expression levels. In vitro and in vivo experiments were used to investigate the role of MS4A4A in regulating M2 polarization and contributing to malignant behaviour in glioma. We found that MS4A4A was associated with the macrophages' M2 scores and the prognosis of GBM patients. MS4A4A had a higher expression level in M2 polarization macrophages. MS4A4A regulates macrophage M2 polarisation through NF-κB and JAK-STAT6 signalling pathways. Macrophages with MS4A4A overexpression promoted the proliferation, invasion, and TMZ-resistance of glioma cells in vitro and in vivo experiments. The treatment targeting the MS4A4A/ NF-κB/STAT6 axis could improve the prognosis and TMZ-resistance in the glioma mouse model. The present study revealed the novel mechanism of the MS4A4A regulating macrophages M2 polarization, contributing to the formation of immunosuppressive tumor microenvironment in glioma through NF-κB/STAT6 signaling pathways, which promotes the malignant biological process of glioma cells. Our results provided new evidence that NF-κB and STAT6 inhibitors might be a potential adjuvant agent in overcoming MS4A4A-mediated chemotherapy resistance in glioma.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147778042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial Expression of Concern: p53 promotes adenoviral replication and increases late viral gene expression","authors":"J. A. Royds,&nbsp;M. Hibma,&nbsp;B. R. Dix,&nbsp;L. Hananeia,&nbsp;I. A. Russell,&nbsp;A. Wiles,&nbsp;D. Wynford-Thomas,&nbsp;A. W. Braithwaite","doi":"10.1038/s41388-026-03811-y","DOIUrl":"10.1038/s41388-026-03811-y","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 20","pages":"1953-1953"},"PeriodicalIF":7.3,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03811-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777830","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":"Fibroblast dynamics in colorectal cancer: stability, plasticity, and novel markers.","authors":"Richard Demmler, Charles G Anchang, Yongsong Yong, Andreas Ramming, Simon Rauber, Vera S Schellerer, Benjamin Schmid, Arndt Hartmann, Susanne Merkel, Katharina Imkeller, Elisabeth Naschberger, Michael Stürzl","doi":"10.1038/s41388-026-03809-6","DOIUrl":"https://doi.org/10.1038/s41388-026-03809-6","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is one of the most commonly diagnosed and globally spread malignant diseases. Cancer-associated fibroblasts (CAFs) are key architects of the tumor microenvironment, yet their origin, stability, and interconvertibility remain poorly understood. Using transcriptomic profiling of fibroblasts from colorectal cancer (CRC) patients, we identify highly expressed (HEX) markers that define fibroblast subpopulations and uncover mechanisms governing their plasticity. We find that ADH1B marks normal colon-associated fibroblasts (NAFs), which consist of PI16-NAFs and ADAMDEC1-NAFs. ITGA3 delineates the total CAF population, which comprises myofibroblastic CAFs (myCAFs), whose characterizing markers were associated with poor prognosis and proteolytic inflammatory CAFs (piCAFs), characterized by markers not associated with prognosis. An AGT/TGM2-expressing fibroblast subset is present in both healthy and tumor tissues, suggesting alternative trajectories to the classical NAF-to-CAF transition model. While PI16-NAFs, AGT/TGM2-fibroblasts, and myCAFs maintain stable identities in long-term culture, the ADAMDEC1-NAF and piCAF phenotypes are lost in vitro. ITGA3-CAFs demonstrate dynamic plasticity, with TGF-β stably inducing myCAF formation and TNF-α or inhibition of DNA methylation promoting transient piCAF emergence. These findings redefine fibroblast heterogeneity in CRC and reveal a coexisting stable and plastic fibroblast network that may be amenable to modulation and provides a framework for future functional and translational studies. We identified highly expressed markers (HEX markers) to distinguish CAFs, NAFs and corresponding subpopulations in CRC. ADH1B characterized NAFs, which consisted of stable (solid outline) PI16-NAFs and unstable (dashed outline) ADAMDEC1-NAFs. ITGA3 identified CAFs consisting of stable myCAFs associated with poor prognosis and unstable piCAFs not associated with prognosis. AGT/TGM2 fibroblasts did not express ADH1B or ITGA3, were stable in culture and could be detected in both healthy colon and CRC. Treatment of PI16-NAFs with LPS or IFN-γ induced ADAMDEC1-NAFs, TGF-β the formation of myCAFs, while treatment with TNF-α led to the formation of piCAFs. Reduced DNA methylation converted myCAFs and PI16-NAFs into piCAFs.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}