Cellular Oncology最新文献

{"title":"Genomic diversity and BCL9L mutational status in circulating tumor cells predict overall survival in metastatic colorectal cancer.","authors":"Joao M Alves, Nuria Estévez-Gómez, Roberto Piñeiro, Laura Muinelo-Romay, Patricia Mondelo-Macía, Mercedes Salgado, Agueda Iglesias-Gómez, Laura Codesido-Prada, Astrid Diez-Martín, Joaquin Cubiella, David Posada","doi":"10.1007/s13402-025-01109-x","DOIUrl":"https://doi.org/10.1007/s13402-025-01109-x","url":null,"abstract":"<p><strong>Background: </strong>Metastatic colorectal cancer (mCRC) remains a major cause of cancer-related mortality, but few noninvasive biomarkers exist to track disease progression or inform treatment strategies. Circulating tumor cells (CTCs) offer a minimally invasive source of tumor material, yet the prognostic significance of their genomic diversity remains unclear.</p><p><strong>Methods: </strong>We conducted whole-exome sequencing of CTC pools from 29 mCRC patients to characterize their mutational landscape and assess associations with overall survival.</p><p><strong>Results: </strong>Our analysis revealed substantial variation in mutational burden among patients, with all CTC pools harboring non-silent mutations in key CRC driver genes. Higher genomic diversity in CTC pools was significantly associated with reduced overall survival. Additionally, non-silent mutations in BCL9L emerged as a strong predictor of patient survival.</p><p><strong>Conclusion: </strong>Genomic diversity and BCL9L mutational status in CTC pools emerged as strong predictors of survival in mCRC, underscoring the potential of CTC genomic profiling as a minimally invasive and clinically relevant prognostic tool in mCRC.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234052","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}

{"title":"A novel β-carboline alkaloid derivative targeting MDM2-p53 pathway suppresses colorectal cancer progression.","authors":"Fanbin Zeng, Cheng Chen, Zhanwei Fu, Haihui Huang, Wenqiang Cui, Yuanyuan Zhou, Yanjie Kong, Xia Liu, Zhiru Xu, Shouguo Wang, Tian Xiao, Houjun Xia","doi":"10.1007/s13402-025-01111-3","DOIUrl":"https://doi.org/10.1007/s13402-025-01111-3","url":null,"abstract":"<p><strong>Purpose: </strong>Colorectal cancer (CRC) remains a major global health challenge, necessitating novel therapeutic approaches. β-carboline alkaloids, natural compounds with anticancer properties, have shown potential to inhibit cancer cell viability. Here, we synthesized β-carboline derivatives and explored their potential as CRC inhibitors.</p><p><strong>Methods: </strong>The IC₅₀ values of β-carboline derivatives were determined by cell viability assay. The biological effects of the leading candidate were evaluated via cell cycle analysis, proliferation assay, colony formation, apoptosis assay, and reactive oxygen species detection. Mechanistic studies were performed using transcriptomic and proteomic analysis, validated by immunoblotting, pulldown assay, cycloheximide-chasing assay, and co-immunoprecipitation. An in vivo CRC xenograft model was used to assess the efficacy of the leading candidate.</p><p><strong>Results: </strong>Z-7 was identified as the leading candidate due to its ability to induce apoptosis and cell cycle arrest in CRC cells. Transcriptomic and proteomic data revealed that Z-7 activated the p53 signaling pathway in p53 wild-type CRC by binding to MDM2 at the RING domain, and inhibiting the E3 ligase activity of MDM2, leading to the reduction of p53 ubiquitination. In vivo study showed Z-7 treatment elevated p53 expression and significantly suppressed tumor growth in xenograft models.</p><p><strong>Conclusion: </strong>Z-7 is a promising candidate for CRC therapy, particularly in patients with functional p53 and elevated MDM2, warranting further clinical evaluation.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234089","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}

{"title":"TAK-981 potentiates doxorubicin immunocide in triple-negative breast cancer by IFN I-dependent NK cell stimulation.","authors":"Jia Liu, Yiming Wang, Xiaoxia Wei, Suyan Liu, Congting Hu, Pingping Peng, Wenhua Wu, Jiaqin Cai, Hong Sun","doi":"10.1007/s13402-025-01114-0","DOIUrl":"https://doi.org/10.1007/s13402-025-01114-0","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to investigate the synergistic antitumor effects and immunoregulatory functions of the SUMOylation inhibitor TAK-981 in combination with the chemotherapeutic agent doxorubicin (DOX) in triple-negative breast cancer (TNBC), as well as to evaluate the safety of this combination strategy, particularly its mitigating effect on DOX-induced cardiotoxicity.</p><p><strong>Methods: </strong>In vitro experiments were conducted to assess the effects of TAK-981 and DOX, both alone and in combination, on the type I interferon (IFN I) signaling pathway, cell proliferation, and apoptosis in TNBC cells. Mechanistic studies were performed to explore their impact on the IFN I/JAK1/STAT1 axis and the expression of the downstream NKG2D ligand NKG2DL (ULBP2). In vivo animal models were used to evaluate the antitumor efficacy of the combination therapy, its effect on natural killer (NK) cell activity, systemic toxicity, with a focus on its cardioprotective effects.</p><p><strong>Results: </strong>TAK-981 activated IFN I signaling, and DOX further enhanced IFN I pathway activity. The two drugs demonstrated a synergistic effect, significantly inducing apoptosis and inhibiting proliferation in TNBC cells. Mechanistically, the TAK-981 and DOX combination targeted the IFN I/JAK1/STAT1 signaling axis, downregulating the expression of the NKG2D ligand (ULBP2) through suppression of the NF-κB pathway. In vivo experiments confirmed that the combination therapy effectively inhibited tumor growth, enhanced NK cell activity, and did not increase systemic toxicity. Notably, TAK-981 significantly alleviated DOX-induced cardiotoxicity, improved cardiac function, and reduced fibrosis.</p><p><strong>Conclusion: </strong>The combination of an immunomodulatory agent with chemotherapy represents a novel therapeutic strategy for TNBC. TAK-981 not only synergizes with DOX to produce antitumor immun effects but also significantly mitigates DOX-induced cardiotoxicity, offering a promising new direction for improving the efficacy and safety of TNBC treatment.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234043","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}

{"title":"Mendelian analysis reveals novel pancreatic cancer-associated gut bacteria with tumor-suppressive effects.","authors":"Yi Tong, Qian Li, Wei Zhang, Xingli Fan, Hong Tu, Yu Gan","doi":"10.1007/s13402-025-01098-x","DOIUrl":"https://doi.org/10.1007/s13402-025-01098-x","url":null,"abstract":"","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145132320","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}

{"title":"PTEN loss and ERBB2/ERBB3-mediated AKT reactivation drive resistance to MET inhibition in MET-amplified hepatocellular carcinoma.","authors":"Ruolan Qian, Yuchen Guo, Xiaolin Hu, Jing Ling, Haigang Geng, Qiaoqiao Ye, Linmeng Zhang, Shujie Zhan, Long Liao, Yang Ge, Quan Zheng, Ying Cao","doi":"10.1007/s13402-025-01097-y","DOIUrl":"https://doi.org/10.1007/s13402-025-01097-y","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to limited treatment options and frequent resistance to targeted therapies. MET amplification is a promising therapeutic target in a subset of HCC. However, mechanisms of resistance to MET inhibitors are not fully understood, impeding the efficacy of treatments.</p><p><strong>Methods: </strong>We performed a genome-wide CRISPR-Cas9 screen to identify genetic determinants of resistance to MET inhibitors. The efficacy of selective MET inhibitors, including capmatinib and tepotinib, was evaluated in MET-amplified HCC models. Mechanistic studies were conducted to characterize AKT signaling dynamics and tumour cell responses under various treatment conditions.</p><p><strong>Results: </strong>MET inhibitors selectively suppressed tumour growth in MET-amplified HCC. However, PTEN deficiency sustained AKT activation despite MET blockade, facilitating tumour survival. Moreover, MET inhibitor treatment triggered adaptive upregulation of ERBB2/ERBB3, leading to AKT reactivation and resistance. Combined inhibition of MET and AKT or ERBB kinases synergistically restored therapeutic response and induced apoptosis. These resistance mechanisms also reduced the efficacy of cabozantinib. Notably, neither combination was effective in MET-high non-amplified HCC.</p><p><strong>Conclusion: </strong>Our study identifies PTEN deficiency and ERBB2/ERBB3-mediated reactivation as key resistance mechanisms to MET inhibition in MET-amplified HCC. The findings support biomarker-informed combination strategies and underscore the importance of stratifying patients based on MET amplification status.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145132325","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}

{"title":"The m¹A-SFRP2-NFAT/TOX axis governs T cell exhaustion in gastric cancer.","authors":"Yifan Liu, Gege Liu, Xuanlin Wang, Xueru Zhang, Junlu Wu, Yaran Li, Yao Lu, Ce Shi, Feng Ye, Ruixin Sun","doi":"10.1007/s13402-025-01096-z","DOIUrl":"https://doi.org/10.1007/s13402-025-01096-z","url":null,"abstract":"<p><strong>Background: </strong>While immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, their efficacy in gastric cancer (GC) remains limited, underscoring the need for mechanistic biomarkers of immune evasion.</p><p><strong>Methods: </strong>We analyzed m¹A RNA modification patterns in the TCGA-STAD cohort, stratifying patients into three subtypes. Functional assays (including CRISPR-based SFRP2 modulation, NFAT/TOX reporter systems, and ex vivo T-cell exhaustion models) were employed to dissect the m1A-SFRP2-NFAT/TOX axis.</p><p><strong>Results: </strong>High-m¹A tumors exhibited an immunosuppressive microenvironment dominated by exhausted TIM-3⁺PD-1⁺ T cells and poor ICIs responses. Mechanistically, m¹A-modified transcripts stabilized SFRP2, which activated NFAT1/2-TOX signaling to drive T-cell dysfunction-independent of PD-L1 or TMB. SFRP2 overexpression induced irreversible T-cell exhaustion, while its blockade restored antitumor immunity in preclinical models.</p><p><strong>Conclusion: </strong>Our study unveils m¹A-dependent epitranscriptomic control of SFRP2 as a novel regulator of the NFAT/TOX-mediated immune evasion axis in GC. The m¹A scoring system may refine patient stratification, and targeting SFRP2 represents a promising strategy to overcome ICI resistance.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144818034","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}

{"title":"HBO1 determines epithelial-mesenchymal transition and promotes immunotherapy resistance in ovarian cancer cells.","authors":"Cong Zhang, Jinmin Zhu, Huaisong Lin, Zhishuai Zhang, Baoqiang Kang, Fei Li, Yongli Shan, Yanqi Zhang, Qi Xing, Jiaming Gu, Xing Hu, Yuanbin Cui, Jingxi Huang, Tiancheng Zhou, Yuchan Mai, Qianyu Chen, Rui Mao, Peng Li, Guangjin Pan","doi":"10.1007/s13402-025-01055-8","DOIUrl":"10.1007/s13402-025-01055-8","url":null,"abstract":"<p><strong>Purpose: </strong>Epithelial-mesenchymal transition (EMT) plays critical roles in tumor progress and treatment resistance of ovarian cancer (OC), resulting in the most deadly gynecological cancer in women. However, the cell-intrinsic mechanism underlying EMT in OC remains less illuminated.</p><p><strong>Method: </strong>SKOV3, the OC cell line, was treated with TGF-β to induce EMT or with SB431542, an inhibitor of the TGF-β signaling pathway, to reduce migration. The function of HBO1 in EMT was confirmed by knock-down or overexpression of HBO1 in SKOV3 cells. The role of HBO1 in cell proliferation and apoptosis of SKOV3 cells was analyzed by flow cytometry. The whole-genome transcriptome was used to compare significantly different genes in control and HBO1-KD SKOV3 cells. T-cell cytotoxicity assays were measured by an IVIS spectrum. The chromatin binding of HBO1 was investigated using CUT&Tag-seq.</p><p><strong>Results: </strong>Here, we show that HBO1, a MYST histone acetyltransferase (HAT), is a cell-intrinsic determinant for EMT in OC cells. HBO1 is greatly elevated during TGF-β-triggered EMT in SKOV3 OC cells as well as in later stages of clinical OC samples. HBO1 Knock-down (KD) in SKOV3 cells blocks TGF-β-triggered EMT, migration, invasion and tumor formation in vivo. Interestingly, HBO1 KD in SKOV3 cells suppresses their resistance to CAR-T cells. Mechanistically, HBO1 co-binds the gene sets responsible for EMT with SMAD4 and orchestrates a gene regulatory network critical for tumor progression in SKOV3 cells.</p><p><strong>Conclusion: </strong>HBO1 plays an essential onco-factor to drive EMT and promote the immunotherapy resistance in ovarian cancer cells. Together, we reveal a critical role of HBO1 mediated epigenetic mechanism in OC progression, providing an insight into designing new therapy strategies.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"943-959"},"PeriodicalIF":4.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991933","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}

{"title":"Trained immunity alleviates the progression of melanoma during sepsis-associated immunoparalysis.","authors":"Lijie Yin, Yue Dong, Renjie Luo, Jingman Li, Jiali Wang, Huan Dou, Guangfeng Zhao, Yayi Hou","doi":"10.1007/s13402-025-01063-8","DOIUrl":"10.1007/s13402-025-01063-8","url":null,"abstract":"<p><strong>Background: </strong>Patients who survive the excessive inflammatory phase of sepsis experience prolonged immunoparalysis/immunosuppression. During this phase, the patient's immune system is severely impaired, which increases the patient's susceptibility to septic complications. Sepsis survivors have a significantly greater incidence of cancer, but the mechanism underlying this phenomenon is unknown.</p><p><strong>Methods: </strong>We constructed two sepsis-melanoma models to assess the relationship between sepsis and sepsis-related concomitant cancer. In our investigation, we employed a range of experimental technique to elucidate the intricate mechanisms through which the immunoparalysis phase of sepsis facilitates melanoma progression. Furthermore, we induced trained immunity with oroxylin A (OA) to evaluate its ability to reverse immunoparalysis and subsequent tumor progression in sepsis-melanoma models.</p><p><strong>Results: </strong>We showed that sepsis upregulated the serum level of interleukin (IL)-6 and the number of myeloid-derived suppressor cells (MDSCs), regulated G-MDSCs/M-MDSCs and inhibited CD8⁺T-cell function, which promoted melanoma progression. OA-induced trained immunity can reverse immunoparalysis, maintain the antitumor capacity of the immune system, and inhibit the development of sepsis-complicated melanoma. Notably, OA can target macrophage migration inhibitory factor (MIF) and downregulate the serum level of IL-6, which may be a crucial molecular mechanism by which OA induces trained immunity to reverse the immunoparalysis phase of sepsis.</p><p><strong>Conclusion: </strong>Sepsis can promote cancer progression by upregulating MIF and IL-6, increasing the G-MDSCs/M-MDSCs ratio and reducing the number and function of CD8⁺ T cells, leading to immunoparalysis, while trained immunity can alleviate this progression. The findings of this study provide new strategies for preventing or treating sepsis-complicated cancer.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1047-1065"},"PeriodicalIF":4.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023938","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}

{"title":"Neuregulin-induced HER3 activation drives migration in head and neck squamous cell carcinoma via HER2 and FAK signaling pathways.","authors":"Eun Jin Lim, Yu Jeong Yoon, Jeonghoon Heo, Seungwon Kim, Yung-Hyun Choi, Young-Ho Kim","doi":"10.1007/s13402-025-01069-2","DOIUrl":"10.1007/s13402-025-01069-2","url":null,"abstract":"<p><strong>Purpose: </strong>To investigate the role of neuregulin (NRG) signaling in promoting head and neck squamous cell carcinoma (HNSCC) migration through HER3-dependent pathways and to assess the therapeutic potential of targeting the NRG/HER3 axis in mitigating perineural invasion.</p><p><strong>Methods: </strong>NRG-driven migration was studied using DRG co-culture, wound healing assays, and HER3 inhibition (shRNA, AV-203). The biological function and biochemical effects of the HER3/HER2/FAK axis in response to NRG were analyzed via phosphorylation assays, knockdown, western blotting, and cell staining for protein expression.</p><p><strong>Results: </strong>NRG promoted directional migration of FaDu and TU138 HNSCC cells through HER3/HER2 and HER3/PI3K interactions. HER3 inhibition (shRNA or AV-203) abolished HER3 phosphorylation, disrupted HER3-HER2 interactions, and suppressed AKT and ERK signaling. Wound healing assays confirmed that NRG enhances migration via HER3 activation. NRG also induced HER3-dependent FAK phosphorylation, and FAK knockdown or inhibition with PF228 significantly reduced NRG-driven migration, highlighting the critical role of HER3-FAK signaling.</p><p><strong>Conclusion: </strong>NRG promotes HNSCC cell migration by activating HER3, forming HER3-HER2 and HER3-FAK complexes, and driving downstream AKT, ERK, and FAK signaling. Targeting the NRG/HER3 axis holds potential as a therapeutic strategy to address perineural invasion and associated clinical challenges in HNC.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1089-1103"},"PeriodicalIF":4.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043944","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}

{"title":"THEMIS2 contributes to ovarian cancer metastasis via DOCK4-mediated activation of Rap1 signaling.","authors":"Kaixia Zhou, Xiaolu Ma, Tianqing Yan, Ling Hu, Yanan Tian, Hui Zheng, Suhong Xie, Ying Tong, Yanchun Wang, Lin Guo, Renquan Lu","doi":"10.1007/s13402-025-01057-6","DOIUrl":"10.1007/s13402-025-01057-6","url":null,"abstract":"<p><strong>Purpose: </strong>Ovarian cancer (OC) is the most lethal gynecological malignancy, with widespread metastasis and ascites being the leading causes of patient mortality. However, the mechanisms driving OC metastasis have not been sufficiently studied. This study aimed to investigate the mechanisms and key molecules promoting OC metastasis.</p><p><strong>Methods: </strong>Public databases (StemChecker, GeneCards, GEO, and TCGA) were screened to identify metastasis-associated genes. Immunohistochemical staining and western blotting were employed to evaluate THEMIS2 expression and epithelial-mesenchymal transition (EMT) marker profiles across experimental groups. RNA sequencing coupled with pathway enrichment analysis revealed THEMIS2-regulated signaling pathways, while immunoprecipitation-mass spectrometry was utilized to identify THEMIS2 interaction partners. GST pull-down assays for active Rap1 quantified Rap1-GTP levels under varying THEMIS2 expression conditions. Wound healing and transwell invasion assays respectively assessed migratory and invasive capacities of OC cells following THEMIS2 expression perturbations in vitro. Abdominal cavity implantation metastasis model was established to evaluate OC cell colonization and invasive potential in vivo.</p><p><strong>Results: </strong>THEMIS2 expression is significantly elevated in OC tissues compared to normal ovarian tissues, and its high expression correlates with poor prognosis and malignant features. Experimental manipulation of THEMIS2 levels revealed that knockdown impended the migratory and invasive capacities of OC cells both in vitro and in vivo, while its overexpression exacerbated metastasis. THEMIS2 is involved in EMT and cytoskeleton rearrangement. RNA-seq analysis revealed that THEMIS2 positively correlates with Rap1 signaling pathway. Inhibition of Rap1 activity reversed the metastasis-promoting effects induced by THEMIS2 overexpression both in vitro and in vivo. Mechanistically, we uncovered that THEMIS2 functions as a molecular scaffold that recruits TBK1 (TANK Binding Kinase 1) to DOCK4 (Dedicator of Cytokinesis 4), facilitating site-specific phosphorylation at serine 1787 (S1787). This post-translational modification enables DOCK4 to engage with CRKII, subsequently triggering Rap1 signaling activation. These findings suggest that THEMIS2 promotes the metastatic potential of OC cells via DOCK4-mediated activation of Rap1 signaling.</p><p><strong>Conclusion: </strong>THEMIS2 may serve as a predictive biomarker for OC prognosis, and targeting the Rap1 signaling pathway with specific inhibitors represents a promising therapeutic strategy for OC treatment.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"961-978"},"PeriodicalIF":4.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144040377","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}