Cancer Science最新文献

{"title":"Androgen Receptor-Controlled microRNA-124-3p.2 Suppresses Prostate Cancer Progression via CCL2 Inhibition","authors":"Shuhei Aoyama,&nbsp;Kouji Izumi,&nbsp;Kaoru Hiratsuka,&nbsp;Takahiro Inaba,&nbsp;Yoshiki Koketsu,&nbsp;Ryunosuke Nakagawa,&nbsp;Ren Toriumi,&nbsp;Taiki Kamijima,&nbsp;Hiroshi Kano,&nbsp;Tomoyuki Makino,&nbsp;Renato Naito,&nbsp;Suguru Kadomoto,&nbsp;Hiroaki Iwamoto,&nbsp;Hiroshi Yaegashi,&nbsp;Shohei Kawaguchi,&nbsp;Kazuyoshi Shigehara,&nbsp;Takahiro Nohara,&nbsp;Hiroki Nakata,&nbsp;Yohei Saito,&nbsp;Kyoko Nakagawa-Goto,&nbsp;Wen-Jye Lin,&nbsp;Atsushi Mizokami","doi":"10.1111/cas.70157","DOIUrl":"10.1111/cas.70157","url":null,"abstract":"<p>We previously reported that androgen receptor (AR) signaling blockade induces chemotactic-C–C-motif-chemokine-ligand-2 (CCL2) secretion from prostate cancer cells and activates cancer cells through an autocrine manner. However, the mechanism of how AR negatively regulates CCL2 expression is still unclear. As various microRNAs participate in prostate cancer development, we hypothesized that there are AR-controlled miRs that regulate CCL2 production. Using LNCaP and C4-2B cells, miR-124-3p.2 was found as a potential miR from the miRNA PCR array and public database. The expression of miR-124-3p.2 was inhibited by knockdown AR, and the introduction of miR-124-3p.2 mimic decreased CCL2 expression and suppressed cell migration. Dihydrotestosterone led to miR-124-3p.2 upregulation and CCL2 downregulation. To examine whether miR-124-3p.2 and CCL2 are involved in prostate cancer progression, their expression levels and clinical parameters were analyzed using prostate biopsy samples and whole blood RNAs obtained from the biopsied patients. Patients with low miR-124-3p.2 and high CCL2 levels showed a shorter time to castration-resistant prostate cancer development than those with high miR-124-3p.2 and low CCL2 levels. Our study demonstrated that AR suppresses CCL2 expression via miR-124-3p.2, and the miR-124-3p.2-CCL2 axis may be a novel therapeutic target and a useful blood prognostic biomarker for advanced prostate cancer.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 10","pages":"2797-2807"},"PeriodicalIF":4.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70157","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692179","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":"Real-World Comparison of Gene-Matched vs. Non-Gene-Matched Therapy Outcomes Using Integrated Genomic and Clinical Data","authors":"Taisuke Ishii,&nbsp;Takashi Kohno,&nbsp;Takashi Yugawa,&nbsp;Tatsuya Suzuki,&nbsp;Takafumi Koyama,&nbsp;Takahiro Higashi,&nbsp;Hiroyuki Mano,&nbsp;Yusuke Okuma","doi":"10.1111/cas.70146","DOIUrl":"10.1111/cas.70146","url":null,"abstract":"<p>Previous studies have demonstrated that 10%–25% of patients receive gene-matched therapy (GMT) after comprehensive genomic profiling (CGP). However, its real-world clinical effects remain unclear. This study assessed the feasibility of integrating the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) repository that documented genomic and clinical data and the quality indicator (QI) dataset that included cancer-specific data and administered treatment as a model case of real-world data study of cancer genomic medicine in Japan. We successfully integrated these two datasets and included 1162 patients diagnosed with solid tumors at the National Cancer Center Hospital between 2019 and 2021 who underwent CGP testing. Of these, 432 (37.2%) had druggable mutations, 96 (8.3%) received GMT, and 218 (18.8%) received non-GMT. Among 314 patients who initiated either GMT or non-GMT after CGP, the median 2-year overall survival (OS) was 19.0 and 19.7 months for GMT and non-GMT, respectively (hazard ratio: 0.87, 95% confidence interval: 0.56–1.35, <i>p</i> = 0.53). Stratified analysis by prior treatment lines (0–1 vs. ≥ 2) demonstrated no significant differences in survival. Sensitivity analyses yielded consistent results. This study demonstrated that integrating the C-CAT repository and QI datasets enables real-world comparisons of GMT and non-GMT outcomes. Unlike previous clinical trials reporting enhanced survival with GMT, our findings indicated no significant OS difference. Potential explanations include differences in cancer type, CGP timing, study population selection, and immortal time bias. Future multicenter studies would clarify the real-world utility of the CGP and GMT.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 10","pages":"2788-2796"},"PeriodicalIF":4.3,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70146","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683509","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":"Correction to “Long noncoding RNA SNHG3 interacts with microRNA-502-3p to mediate ITGA6 expression in liver hepatocellular carcinoma”","authors":"","doi":"10.1111/cas.70155","DOIUrl":"10.1111/cas.70155","url":null,"abstract":"<p>Guo Guo J, Zhang J, Xiang Y, Zhou S, Yang Y, Zheng J. Long noncoding RNA SNHG3 interacts with microRNA-502-3p to mediate ITGA6 expression in liver hepatocellular carcinoma. <i>Cancer Sci</i>. 2024;115:2286-2300. https://doi.org/10.1111/cas.16190.</p><p>In the above article, Dr. Jinfang Zheng's affiliation is incorrect. The correct affiliation is shown below:</p><p>Department of Hepatobiliary Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, Hainan, P.R. China.</p><p>We apologize for this error.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70155","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668795","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":"Prognostic and Predictive Value of Machine Learning-Based Biomarker and Pathomics Signatures in Patients With Prostate Cancer","authors":"Jianpeng Zhang,&nbsp;Jinyou Pan,&nbsp;Jingwei Lin,&nbsp;Yingxin Cai,&nbsp;Yangzhou Liu,&nbsp;Fuyang Lin,&nbsp;Hantian Guan,&nbsp;Gaoxiang Zhou,&nbsp;Daqiang Wei,&nbsp;Zuomin Wang,&nbsp;Yuxiang Ma,&nbsp;Zhigang Zhao","doi":"10.1111/cas.70149","DOIUrl":"10.1111/cas.70149","url":null,"abstract":"<p>Recurrence and the potential development of castration resistance after radical prostatectomy (RP) are significant challenges in the management of prostate cancer (PCa). Despite the development of advanced prognostic models, few have been clinically applied. Five machine learning algorithms (LASSO, RSF, SVM-RFE, Boruta, and XGBoost) were used to identify biomarkers for PCa using transcriptome data from multicenters (TCGA, MSKCC, DKFZ, and GSE70770) for constructing and validating the metastasis-associated prognostic risk score (MAPRS), which revealed the molecular biological heterogeneity and was confirmed with in-house histopathological samples. The pathomics score (PSpc), derived from a machine learning framework (XGBoost, RSF, GBM, plsRCox, CoxBoost, Enet, Ridge, LASSO, SVM, and superPC) using hematoxylin and eosin (H&amp;E)-stained digital pathology, quantified tumor morphological heterogeneity. The MAPRS correlated with poorer recurrence-free survival (RFS) and was associated with the tumor microenvironment and pathogenic variants. A higher MAPRS may indicate sensitivity to treatments such as PARP inhibitors, docetaxel, and oxaliplatin. Pathology-based evaluations of MAPRS, PSpc, and their combination effectively predicted RFS in patients who underwent RP. MAPRS also predicted progression-free survival in patients receiving androgen deprivation therapy when combined with clinical indicators, whereas PSpc demonstrated limited efficacy. The digital pathology-based signatures showed superior predictive efficacy compared to other tools.</p><p><b>Trial Registration:</b> Chinese Clinical Trial Registry number: ChiCTR2400085748 (June 18, 2024).</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 10","pages":"2893-2906"},"PeriodicalIF":4.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70149","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144660861","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":"HROB Induces Lung Adenocarcinoma Progression via ZC3HC1-CCNB1 Axis Regulation and Cell Cycle Dysregulation","authors":"Zhe Zhang,&nbsp;Cheng Wang,&nbsp;Yuanwei Guo,&nbsp;Zhenyu Zhao,&nbsp;Zhi Yang,&nbsp;Shouzhi Xie,&nbsp;Xinhang Hu,&nbsp;Xingchun Huang,&nbsp;Yupeng Jiang,&nbsp;Bing Xiao,&nbsp;Li Wang,&nbsp;Fenglei Yu,&nbsp;Bin Wang","doi":"10.1111/cas.70141","DOIUrl":"10.1111/cas.70141","url":null,"abstract":"<p>Lung adenocarcinoma (LUAD), a leading cause of cancer-related mortality, remains a significant global health challenge due to limited understanding of its molecular mechanisms. HROB, a recently identified gene, has been implicated in cell cycle regulation, but its role in lung cancer progression is poorly understood. In this study, we demonstrate that HROB suppresses LUAD progression by interacting with ZC3HC1 and reducing its phosphorylation at Ser354. This de-phosphorylation event facilitates K27-linked ubiquitination of CCNB1, promoting its proteasomal degradation and impairing the G2-to-M phase transition. Consequently, HROB suppresses cell proliferation and tumor growth. Our findings reveal a novel HROB–ZC3HC1–CCNB1 regulatory axis, providing mechanistic insights into LUAD progression. These results highlight HROB as a potential therapeutic target, offering new avenues for clinical intervention in lung cancer treatment.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 10","pages":"2699-2711"},"PeriodicalIF":4.3,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70141","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144627456","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":"Correction to “Quadruple-editing of the MAPK and PI3K pathways effectively blocks the progression of KRAS-mutated colorectal cancer cells”","authors":"","doi":"10.1111/cas.70145","DOIUrl":"10.1111/cas.70145","url":null,"abstract":"<p>Wang Z, Kang B, Gao Q, et al. Quadruple-editing of the MAPK and PI3K pathways effectively blocks the progression of KRAS-mutated colorectal cancer cells. <i>Cancer Sci</i>. 2021;112:3895–3910. https://doi.org/10.1111/cas.15049</p><p>We apologize for this error.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70145","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144638519","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":"NFATc4 Promotes Lung Adenocarcinoma Progression via the CCNB1/CDK1 Pathway and Is a Potential Prognostic Biomarker","authors":"Wendi Yang,&nbsp;Xue Wu,&nbsp;Fanghao Cai,&nbsp;Zhengjun Guo,&nbsp;Zaicheng Xu,&nbsp;Yuan Peng,&nbsp;Zhenzhou Yang,&nbsp;Xiaoyue Zhang","doi":"10.1111/cas.70122","DOIUrl":"10.1111/cas.70122","url":null,"abstract":"<p>Nuclear factor of activated T-cells, cytoplasmic 4 (NFATc4), a transcription factor of the NFAT family, has been reported to participate in the tumorigenesis and progression of several cancers. However, the function and regulation of NFATc4 in lung adenocarcinoma (LUAD) remain poorly understood. Here, we report for the first time that NFATc4 is significantly overexpressed in LUAD tissues, and high NFATc4 expression correlates with lymphatic metastasis, advanced tumor stage, and poor prognosis in patients. Subsequent functional studies revealed that NFATc4 depletion inhibits LUAD cell viability, proliferation, and tumor growth by inducing cell cycle arrest in the G2/M phase and apoptosis. A mechanistic study shows that NFATc4 knockdown leads to significant enrichment of cellular process-related pathways and differentially expressed genes, especially downregulated genes Cyclin B1 (CCNB1) and cyclin-dependent kinase 1 (CDK1). NFATc4 directly binds to the CCNB1 promoter to regulate the CCNB1/CDK1 pathway, resulting in cell cycle arrest and inhibition of cell proliferation. This study identifies NFATc4/CCNB1/CDK1 as a novel regulatory pathway involved in LUAD development and provides a potential prognostic biomarker and molecular therapeutic target for LUAD.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 9","pages":"2400-2412"},"PeriodicalIF":4.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70122","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610099","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":"Correction to “Alternative RNA Splicing of the GIT1 Gene Is Associated With Neuroendocrine Prostate Cancer”","authors":"","doi":"10.1111/cas.70140","DOIUrl":"10.1111/cas.70140","url":null,"abstract":"<p>A. R. Lee, Y. Gan, N. Xie, V. R. Ramnarine, J. M. Lovnicki, and X. Dong, “Alternative RNA Splicing of the <i>GIT1</i> Gene Is Associated With Neuroendocrine Prostate Cancer,” <i>Cancer Science</i> 110, no. 1 (2019): 245–255, https://doi.org/10.1111/cas.13869.</p><p>Concerns were raised by a third party regarding image panels with insets without any magnification or scale bar in Figure 2A. The authors acknowledged that these insets were cropped and amplified from the original images; therefore, no scale bar was inserted. The unamplified insets were replaced by the 10× magnified panels accordingly.</p><p>The corrected Figure 2A and its corrected figure caption are as follows:</p><p>\u0000 <b>Figure 2</b>\u0000 </p><p>RNA splicing of <i>GIT1</i> is associated with clinical NEPC tumors. A, RISH probes targeting the exons 7/8 or exons 7/9 junction were created to detect GIT1-A or GIT1-C, respectively, in a human CRPC TMA (n = 64 cores). TMA was stained against CHGA, SYP, CD56, AR, and PSA by immunohistochemistry (IHC). Columns in the heatmap represent one of 64 cores. One representative core from each of the histologically diagnosed AdPC (n = 52), AdNC (n = 6), and SCNC (n = 6) cores is shown. Scale bars represent 25 μm. Insets represent cropped and 10× amplified images.</p><p>In addition, the figure captions of Figures 3A and 5 have also been revised, as follows:</p><p>\u0000 <b>Figure 3</b>\u0000 </p><p>SRRM4 regulates RNA splicing of <i>GIT1</i>. A, Matched TMA cores are shown to represent the associations of the expressions of SRRM4 with GIT1-A and GIT1-C. Scale bars represent 25 μm. Insets represent cropped and 10× amplified images.</p><p>\u0000 <b>Figure 5</b>\u0000 </p><p>Differential functions of the GIT1 splice variants in FA stability. DU145 stable cell lines overexpressing GIT1-A, GIT1-C, or empty vector were seeded on coverslips and serum-starved. They were treated with 10 μmol/L nocodazole for 4 h, subsequently washed away, and replaced with serum-containing medium. Cells were fixed at 0 or 120 min after the washout, costained against GIT1 and vinculin, and then mounted with DAPI staining mount. Cells were imaged using a Zeiss AxioObserver Z1 (Carl Zeiss AG; Oberkochen, Germany) microscope, where the scale bar represents 10 μm. Insets represent cropped and 10× amplified images. Arrowheads indicate FA complexes. Overlapping signals between GIT1 and vinculin appear yellow. Overlapping of the two signals in a cross section (indicated by white line) of FA complexes was profiled by the ZEN program. All experiments were repeated three times. FA, focal adhesion; GIT1, G-protein-coupled receptor kinase-interacting protein 1; IF, immunofluorescence; ZEN, ZEISS efficient navigation.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 9","pages":"2620-2621"},"PeriodicalIF":4.3,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70140","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601959","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":"Antitumor Activity of Tumor-Infiltrating Neutrophils Revealed by a Syngeneic Mouse Model of Cholangiocarcinoma","authors":"Osamu Sugahara,&nbsp;Daisuke Koga,&nbsp;Takeru Oka,&nbsp;Shigeaki Sugiyama,&nbsp;Reona Wada,&nbsp;Tsunaki Higa,&nbsp;Keiichi I. Nakayama","doi":"10.1111/cas.70129","DOIUrl":"10.1111/cas.70129","url":null,"abstract":"<p>The tumor immune microenvironment plays a key role in the regulation of cancer progression. Recent studies have suggested a relation between diverse tumor genotypes and tumor immune microenvironment phenotypes for cholangiocarcinoma (CCA). However, the contribution of tumor-infiltrating immune cells to CCA progression has remained unclear, underscoring the need for genetically defined CCA models in immunocompetent mice. We here aimed to generate genetically engineered and transplantable CCA organoids from C57BL/6 mice and to investigate the role of tumor-infiltrating immune cells in CCA progression with this model. CCA organoids were generated ex vivo with the use of the CRISPR/Cas9 system. Orthotopic transplantation of CCA organoids harboring mutations in <i>Smad4</i>, <i>Trp53</i>, and <i>Kras</i> into wild-type C57BL/6 mice resulted in tumor formation accompanied by distant metastasis. Selective depletion of immune cell types in the tumor-bearing mice revealed an antitumor action of tumor-infiltrating neutrophils (TINs) that was mediated by direct killing of cancer cells through the production of reactive oxygen species. Furthermore, administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) increased the number and cytotoxicity of TINs, suppressed tumor growth, and prolonged the survival of tumor-bearing mice. Finally, combination treatment with rhG-CSF and standard chemotherapy resulted in a synergistic attenuation of tumor growth. Our study therefore provides a syngeneic and genetically defined mouse model of CCA and highlights the therapeutic potential of targeting TINs with rhG-CSF.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 9","pages":"2457-2470"},"PeriodicalIF":4.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70129","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576788","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":"LATS1/2–Integrin Axis Confers Tumor-Generated Forces That Activate Neighboring Fibroblasts","authors":"Yanliang Liu,&nbsp;Saisai Liu,&nbsp;Yasuhisa Sakamoto,&nbsp;Paweenapon Chunthaboon,&nbsp;Chanida Thinyakul,&nbsp;Ryunosuke Mori,&nbsp;Shuran Li,&nbsp;Takahiro Watanabe-Nakayama,&nbsp;Seiji Omata,&nbsp;Yasuyuki Morita,&nbsp;Toshiro Moroishi","doi":"10.1111/cas.70137","DOIUrl":"10.1111/cas.70137","url":null,"abstract":"<p>Tumors generate various forces during growth and progression, which in turn promote tumor development. Although fibroblasts are considered the primary force generators in the tumor microenvironment, recent studies have shown that cancer cells also generate considerable tensile forces. However, the roles that these forces play in the tumor microenvironment and the pathways regulating this process remain largely unknown. Here, we demonstrated that the Hippo pathway-associated kinases, LATS1/2, in cancer cells are essential for collective force generation and fibroblast activation via extracellular matrix-mediated cell–cell interactions. In murine breast cancer 4 T1 spheroids, the deletion of LATS1/2 dampened force generation and disrupted reorganization of the surrounding collagen matrix. LATS1/2-mediated mechanical forces of tumors are required for fibroblast activation and differentiation into mechanoresponsive fibroblasts. Mechanistically, LATS1/2 regulate tumor force generation through the expression of collagen receptor integrins. Our findings not only identify the Hippo pathway as a critical regulator of tumor force generation but also suggest potential strategies for targeting it in cancer therapy from a mechanobiological perspective, offering new avenues in the fight against cancer.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 9","pages":"2486-2498"},"PeriodicalIF":4.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70137","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576789","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}