Oncogenesis最新文献_第2页

Choroid plexus carcinoma: state of the field and emerging directions. 脉络丛癌：领域现状及新兴方向。

IF 6.4 2区医学

Oncogenesis Pub Date : 2026-04-06 DOI: 10.1038/s41389-026-00612-6

Ashley Thompson, Hannah Pescaru, Briana Griffin, Ryann M Fame

{"title":"Choroid plexus carcinoma: state of the field and emerging directions.","authors":"Ashley Thompson, Hannah Pescaru, Briana Griffin, Ryann M Fame","doi":"10.1038/s41389-026-00612-6","DOIUrl":"https://doi.org/10.1038/s41389-026-00612-6","url":null,"abstract":"Choroid plexus carcinoma (CPC) is a class of rare malignant life-threatening pediatric brain tumors, with a median survival of ~2.5-3 years [1, 2]. Recent advances in human genomics, cellular studies, and animal models have improved our understanding of the pathophysiology and molecular characteristics of CPC. However, because this cancer is rare, it remains understudied. This limited research has led to a limited understanding of the tumor's heterogeneity and molecular pathogenesis, resulting in fewer treatment options. Surgical resection remains the most significant contributor to patient survival and is often combined with chemotherapy, but tumors can still recur and metastasize. The post-surgical 5-year survival rate for CPC is only 60-65% and the adjuvant anti-mitotic radiation or chemotherapy included in standard treatment results in lifelong side effects for these children. Here we conduct a systematic review of existing literature and analyze the current body of research on CPC with special focus on preclinical models to highlight progress and barriers while emphasizing important open questions for improving patient treatment and longevity outcomes. This analysis underscores the importance of scholarly discussion and further exploration into the carcinogenesis of CPC.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147628097","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}

引用次数: 0

GPX3 suppresses gallbladder cancer progression by modulating redox balance, glycolysis, and anti-tumor immunity. GPX3通过调节氧化还原平衡、糖酵解和抗肿瘤免疫来抑制胆囊癌的进展。

IF 6.4 2区医学

Oncogenesis Pub Date : 2026-04-02 DOI: 10.1038/s41389-026-00603-7

Zuyi Ma, Jia Sun, Xin Wu, Changzhen Shang, Binglu Li

{"title":"GPX3 suppresses gallbladder cancer progression by modulating redox balance, glycolysis, and anti-tumor immunity.","authors":"Zuyi Ma, Jia Sun, Xin Wu, Changzhen Shang, Binglu Li","doi":"10.1038/s41389-026-00603-7","DOIUrl":"https://doi.org/10.1038/s41389-026-00603-7","url":null,"abstract":"Gallbladder cancer (GBC) is an aggressive malignancy characterized by metabolic plasticity and profound immune evasion. However, the functional role of glutathione peroxidase 3 (GPX3), a secreted antioxidant enzyme, in these processes remains unclear. Multi-omics analyses of paired GBC and adjacent non-tumor tissues revealed consistent downregulation of GPX3, which correlated with reactive oxygen species (ROS) accumulation and enhanced glycolytic activity. Functional restoration of GPX3 in GBC cells reduced intracellular ROS levels, suppressed the expression of glycolysis-related enzymes, and consequently impaired tumor proliferation, migration, and invasion. In xenograft models, GPX3 overexpression markedly attenuated tumor growth and lung metastasis. Notably, GPX3 restoration also enhanced CD8+ T cell infiltration and elevated pro-inflammatory cytokine production, suggesting reversal of tumor-associated immunosuppression. These findings identify GPX3 as a critical tumor suppressor that integrates redox regulation, metabolic reprogramming, and immune activation to restrict malignant progression. Targeting GPX3 or its downstream pathways may represent a promising therapeutic strategy to simultaneously suppress gallbladder cancer aggressiveness and reinforce anti-tumor immunity.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147609430","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}

引用次数: 0

Alternatively activated macrophages cause DNA damage through an arginase 1-mediated bystander effect and promote epithelial cell transformation. 选择性活化的巨噬细胞通过精氨酸酶1介导的旁观者效应引起DNA损伤，促进上皮细胞转化。

IF 6.4 2区医学

Oncogenesis Pub Date : 2026-04-01 DOI: 10.1038/s41389-026-00611-7

Ram Babu Undi, Michael M Sutton, Evan Becker, Marie Gordon, Sara K Vesely, Samantha Ricketts, Rameswari Velayutham, William M Tierney, Courtney W Houchen, Naushad Ali, Mark M Huycke

{"title":"Alternatively activated macrophages cause DNA damage through an arginase 1-mediated bystander effect and promote epithelial cell transformation.","authors":"Ram Babu Undi, Michael M Sutton, Evan Becker, Marie Gordon, Sara K Vesely, Samantha Ricketts, Rameswari Velayutham, William M Tierney, Courtney W Houchen, Naushad Ali, Mark M Huycke","doi":"10.1038/s41389-026-00611-7","DOIUrl":"https://doi.org/10.1038/s41389-026-00611-7","url":null,"abstract":"Colorectal oncogenesis involves progressive genetic and epigenetic alterations in colon epithelial cells. Classically activated M1 macrophages can generate bystander-induced mutations and neoplastic transformation in epithelial cells. Herein, we report a novel mechanism by which alternatively activated M2 macrophages also induce a bystander effect. Similar to M1 macrophages, M2-activated macrophages cause double-strand DNA breaks in targeted epithelial cells, activate multiple signaling pathways, induce a DNA repair response, and transform epithelial cells in vitro. The M2-induced bystander effect occurs through an arginase 1-mediated mechanism. This enzyme is secreted by M2 macrophages and increases extracellular L-ornithine that is imported by target cells. This leads to increased polyamine metabolism and intracellular hydrogen peroxide causing DNA damage. Arginase 1-positive M2-like macrophages were frequently detected in preneoplastic colon adenomas using multiplex immunofluorescence. A greater proportion of activated macrophages was noted in histologically normal colon than in adenomas or stage I colorectal cancer. In addition to M1-like and M2-like activated macrophages, many macrophages in the colon biopsies expressed a hybrid M1/M2 phenotype. Activated macrophages significantly correlated with double-strand DNA damage in colon epithelial cells and DNA damage repair response. These findings define a novel M2-induced bystander effect and support a role for activated macrophages in colorectal cancer initiation and progression.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147593838","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}

引用次数: 0

The oncogenic control of nucleotide synthesis. 核苷酸合成的致癌控制。

IF 6.4 2区医学

Oncogenesis Pub Date : 2026-03-26 DOI: 10.1038/s41389-026-00608-2

Olivia Vidal-Cruchez, Issam Ben-Sahra

{"title":"The oncogenic control of nucleotide synthesis.","authors":"Olivia Vidal-Cruchez, Issam Ben-Sahra","doi":"10.1038/s41389-026-00608-2","DOIUrl":"10.1038/s41389-026-00608-2","url":null,"abstract":"Proliferating cancer cells reprogramme metabolism to secure nucleotides and other macromolecules required for biomass accumulation and genome duplication. Beyond serving as DNA/RNA precursors, nucleotides act as energy currencies, second messengers, glycosyl donors, and modulators of cytoskeletal dynamics; sustaining adequate pools is therefore indispensable for tumour growth and progression. Oncogenic lesions, such as loss of TP53 or LKB1, hyperactive PI3K-AKT-mTORC1, and MYC or RAS, coordinate transcriptional programmes, substrate transport, and post-translational control of rate-limiting enzymes to elevate de novo purine and pyrimidine synthesis and shape salvage use. These circuits integrate glycolysis, the pentose-phosphate pathway, folate-dependent one-carbon metabolism, and glutamine/aspartate provisioning to channel carbon and nitrogen into ring assembly. In this review, we organize this landscape into an environment-shaped routing model that explains when tumours favour de novo versus salvage and how therapies reroute flux. We synthesise current mechanisms by which oncogenes and tumour suppressors regulate nucleotide synthesis in cancer and outline therapeutic implications, including inhibitors of pathway enzymes (e.g., DHODH, IMPDH), strategies that restrict precursor availability, and rational combinations with targeted agents or DNA-damaging therapies to exploit replication stress and metabolic vulnerabilities. Together, these insights highlight nucleotide metabolism as a central, drug-responsive nexus linking oncogenic signalling to malignant proliferation.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13043699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147513866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: LXRα limits TGFβ-dependent hepatocellular carcinoma associated fibroblast differentiation. 更正：LXRα限制tgf β依赖性肝细胞癌相关成纤维细胞分化。

IF 6.4 2区医学

Oncogenesis Pub Date : 2026-03-18 DOI: 10.1038/s41389-026-00610-8

Anita Morén, Claudia Bellomo, Yutaro Tsubakihara, Dimitris Kardassis, Wolfgang Mikulits, Carl-Henrik Heldin, Aristidis Moustakas

引用次数: 0

Teriflunomide modulates the PD-1/PD-L1 axis and enhances antitumor immunity in colorectal cancer. 特立氟米特调节PD-1/PD-L1轴增强结直肠癌的抗肿瘤免疫

IF 6.4 2区医学

Oncogenesis Pub Date : 2026-03-18 DOI: 10.1038/s41389-026-00607-3

Jung Ho Han, Eun-Ji Lee, Young-Hoon Park, Jung-Hye Ha, Kazi Rejvee Ahmed, Jang-Gi Choi, Hwan-Suck Chung

{"title":"Teriflunomide modulates the PD-1/PD-L1 axis and enhances antitumor immunity in colorectal cancer.","authors":"Jung Ho Han, Eun-Ji Lee, Young-Hoon Park, Jung-Hye Ha, Kazi Rejvee Ahmed, Jang-Gi Choi, Hwan-Suck Chung","doi":"10.1038/s41389-026-00607-3","DOIUrl":"10.1038/s41389-026-00607-3","url":null,"abstract":"Inhibitors that target the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint pathway have revolutionized cancer immunotherapy; however, many patients exhibit a limited response. In this study, we examined the potential of teriflunomide (TER), an FDA-approved drug for multiple sclerosis, as a novel immune checkpoint modulator for treating colorectal cancer (CRC). We determined the effect of TER on PD-L1 expression in human CRC cell lines, its direct binding to PD-1, and its impact on CD8+ T-cell function. Antitumor activity was determined in vivo using a humanized mouse model of hPD-1 knock-in mice implanted with hPD-L1 expressing MC38 tumor cells. TER treatment reduced PD-L1 expression in CRC cells and disrupted the PD-1/PD-L1 interaction directly. In vivo, TER significantly suppressed tumor growth without systemic toxicity, and enhanced the infiltration and activation of CD8+ T cells within tumors, as evidenced by increased granzyme B expression. Moreover, the antitumor efficacy of TER was abolished by the depletion of CD8+ T cells, which indicated its dependency on this cell population. These findings highlight TER as a promising immune checkpoint modulator that targets the PD-1/PD-L1 axis to promote CD8+ T-cell-mediated antitumor immunity. Because of its established safety profile, TER is a readily translatable therapeutic for enhancing cancer immunotherapy in CRC.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13002968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147481286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IFFO1 inhibits breast cancer by coordinating mitochondrial fission and fatty acid synthesis via the LaminA/C-PGC1α axis. IFFO1通过LaminA/C-PGC1α轴协调线粒体裂变和脂肪酸合成来抑制乳腺癌。

IF 6.4 2区医学

Oncogenesis Pub Date : 2026-03-17 DOI: 10.1038/s41389-026-00609-1

Huaxia Cai, Jianjun He

{"title":"IFFO1 inhibits breast cancer by coordinating mitochondrial fission and fatty acid synthesis via the LaminA/C-PGC1α axis.","authors":"Huaxia Cai, Jianjun He","doi":"10.1038/s41389-026-00609-1","DOIUrl":"10.1038/s41389-026-00609-1","url":null,"abstract":"Accumulating evidence indicates that mitochondrial dynamics are closely linked to the biological behaviors of tumor cells, with increased mitochondrial fission being recognized as a phenotype that promotes tumor growth. Although intermediate filament family orphan 1 (IFFO1) has been implicated in mitochondrial dynamics, its specific role and molecular mechanisms in regulating mitochondrial fission during breast cancer (BC) progression remain unclear. In this study, analysis of tumor and adjacent normal tissues from 30 BC patients revealed significant downregulation of IFFO1 in tumor tissues, and low IFFO1 expression predicted poor prognosis in patients. In vitro experiments demonstrated that IFFO1 overexpression suppressed the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of BC cells by inhibiting mitochondrial fission and fatty acid synthesis. Mechanistically, IFFO1 interacts with LaminA/C to promote its expression, which subsequently upregulates PGC1α, thereby suppressing mitochondrial fission and fatty acid synthesis in BC cells. Consistent with this mechanism, both LaminA/C and PGC1α were downregulated in BC tissues. Silencing LMNA reversed the inhibitory effects of IFFO1 overexpression on mitochondrial fission and fatty acid synthesis, whereas overexpression of PGC1α effectively counteracted the consequences of LMNA knockdown. In vivo studies confirmed that upregulation of IFFO1 inhibited tumor growth in xenograft models and reduced lung metastasis in a lung metastasis mouse model. These findings underscore the significance of the IFFO1/LaminA/C/PGC1α pathway as a key regulator of mitochondrial fission and fatty acid synthesis during BC progression and highlight its potential as a therapeutic target for breast cancer.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13018651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147474317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of ZBTB7B-mediated ADPGK transcription by NEDD4 impedes glycolysis and progression of lung adenocarcinoma. NEDD4抑制zbtb7b介导的ADPGK转录可阻碍糖酵解和肺腺癌的进展。

IF 6.4 2区医学

Oncogenesis Pub Date : 2026-03-11 DOI: 10.1038/s41389-026-00605-5

Fang-Peng Liu, Ting Huang, Hai-Yan Yang, Jian-Hua Zha, Chuan Xu, Cheng-Peng Qiu, Xing Wang, Zhuo Lu, Tao Wang

{"title":"Inhibition of ZBTB7B-mediated ADPGK transcription by NEDD4 impedes glycolysis and progression of lung adenocarcinoma.","authors":"Fang-Peng Liu, Ting Huang, Hai-Yan Yang, Jian-Hua Zha, Chuan Xu, Cheng-Peng Qiu, Xing Wang, Zhuo Lu, Tao Wang","doi":"10.1038/s41389-026-00605-5","DOIUrl":"10.1038/s41389-026-00605-5","url":null,"abstract":"Lung adenocarcinoma, the predominant type of non-small cell lung cancer, is associated with poor survival outcomes due to late-stage diagnosis, resistance to therapy, and lack of effective metabolic-targeted strategies. Increased glycolysis is a hallmark of LUAD progression, yet the upstream transcriptional and post-translational regulators of glycolytic enzymes remain incompletely defined. This study aims to clarify the molecular mechanisms through which transcription factors and ubiquitin ligases coordinate glycolytic activation and tumor progression in LUAD. We identified ZBTB7B as a transcriptional activator of the non-canonical glycolytic enzyme ADPGK. ZBTB7B expression was significantly increased in LUAD tissues and cell lines, associated with poor prognosis, and enhanced proliferation, migration, and glycolytic flux in an ADPGK-dependent manner. Mechanistically, the E3 ubiquitin ligase NEDD4 directly interacted with ZBTB7B, mediating its ubiquitination at K450 and proteasomal degradation, thereby suppressing ADPGK expression and glycolysis. NEDD4 overexpression suppressed LUAD growth both in vitro and in vivo, effects that were reversed by ZBTB7B restoration. Collectively, this work reveals a novel NEDD4/ZBTB7B/ ADPGK axis that integrates transcriptional and post-translational regulation of glycolysis, offering potential therapeutic targets for metabolic intervention in LUAD.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13002864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147434547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

14,15-epoxyeicosatrienoic acid drives intestinal adenoma growth and its value as an early biomarker for intestinal adenoma occurrence. 14,15-环氧二碳三烯酸驱动肠腺瘤生长及其作为肠腺瘤发生的早期生物标志物的价值。

IF 6.4 2区医学

Oncogenesis Pub Date : 2026-03-11 DOI: 10.1038/s41389-026-00604-6

Shihui He, Ruyu Zeng, Bobing Zheng, Lingbi Jiang, Jinghong Zhu, Jiangchao Li

{"title":"14,15-epoxyeicosatrienoic acid drives intestinal adenoma growth and its value as an early biomarker for intestinal adenoma occurrence.","authors":"Shihui He, Ruyu Zeng, Bobing Zheng, Lingbi Jiang, Jinghong Zhu, Jiangchao Li","doi":"10.1038/s41389-026-00604-6","DOIUrl":"10.1038/s41389-026-00604-6","url":null,"abstract":"Intestinal adenomas are premalignant lesions that develop into colorectal cancer (CRC), yet the metabolic pathways underlying their malignant transformation remain poorly characterized. Using targeted metabolomics via ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we found that serum levels of the bioactive lipid metabolite 14,15-epoxyeicosatrienoic acid (14,15-EET) were dramatically elevated in ApcMin/+ adenoma model mice as early as pre-adenoma stages, compared to C57BL/6 controls. The results were also consistent in adenomas and CRC patients. ELISA data and bioinformatics analyses revealed both elevated serum 14,15-EET levels and upregulated cytochrome P450 2J2 (CYP2J2) expression in tumor. Functional studies showed that 14,15-EET accelerates adenoma growth in vivo, and promotes proliferation, migration, and invasion in vitro by activating AKT (Ser473)/ERK1/2 signaling and inducing epithelial-mesenchymal transition (EMT). Its early elevation in premalignant lesions, and relative molecules 14,15-EET/CYP2J2 represents a novel strategy for disrupting adenoma-carcinoma transition, and offering new biomarker for CRC prevention.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13003130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147434563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

C1s protects cutaneous squamous carcinoma cells from TRAIL-induced apoptosis. C1s保护皮肤鳞状癌细胞免受trail诱导的凋亡。

IF 6.4 2区医学

Oncogenesis Pub Date : 2026-03-07 DOI: 10.1038/s41389-026-00606-4

Maria Salmela, Liisa Nissinen, Pekka Rappu, Kristina Viiklepp, Marjaana Ojalill, Jyrki Heino, Pilvi Riihilä, Veli-Matti Kähäri

{"title":"C1s protects cutaneous squamous carcinoma cells from TRAIL-induced apoptosis.","authors":"Maria Salmela, Liisa Nissinen, Pekka Rappu, Kristina Viiklepp, Marjaana Ojalill, Jyrki Heino, Pilvi Riihilä, Veli-Matti Kähäri","doi":"10.1038/s41389-026-00606-4","DOIUrl":"10.1038/s41389-026-00606-4","url":null,"abstract":"Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. The prognosis of the metastatic cSCC is poor, and there are no established biomarkers to predict metastasis risk, nor specific targeted therapies for advanced or metastatic cSCC. Previous studies have demonstrated that the complement serine proteinase C1s promotes cSCC growth both in culture and in vivo by modulating apoptotic signaling. Here, we investigated the mechanistic role of C1s in regulating apoptosis by examining its impact on cell surface proteome of cSCC cells. Mass spectrometric analysis of cell surface proteins following silencing of C1s identified TRAIL receptor 1 (DR4) as a candidate target, showing increased accumulation at the cell surface. This finding was validated using cell surface biotinylation and western blot analysis in both siRNA-mediated C1s knockdown and CRISPR/Cas9-generated C1s knockout cells. Functionally, high endogenous levels or forced overexpression of C1s conferred resistance to TRAIL-induced apoptosis in cSCC cells, whereas reduced C1s levels sensitized cells to apoptotic signaling. These findings suggest that upregulation of complement C1s in cSCC not only contributes to tumor progression but also serves as a protective mechanism against TRAIL-induced apoptosis, highlighting its potential as a therapeutic target and biomarker in aggressive cSCC.","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12982766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147369841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0