British Journal of Cancer最新文献

{"title":"SMAD2 linker phosphorylation impacts overall survival, proliferation, TGFβ1-dependent gene expression and pluripotency-related proteins in NSCLC","authors":"Dörte Nitschkowski, Tim Vierbuchen, Holger Heine, Jochen Behrends, Norbert Reiling, Martin Reck, Klaus F. Rabe, Christian Kugler, Ole Ammerpohl, Daniel Drömann, Thomas Muley, Mark Kriegsmann, Georgious T. Stathopoulos, Kristina A. M. Arendt, Torsten Goldmann, Sebastian Marwitz","doi":"10.1038/s41416-025-02970-1","DOIUrl":"10.1038/s41416-025-02970-1","url":null,"abstract":"We investigated the impact of SMAD2 linker phosphorylation (pSMAD2L) on overall and disease-free survival, signal transduction, as well as cancer-related processes in non-small cell lung cancer (NSCLC). We generated A549 cells constitutively lacking pSMAD2L (A549Lsub) to gain mechanistic insights and stimulated NSCLC cell lines with inhibitors against cell cycle-associated kinases or TGFβ1. In addition, we analysed SMAD2 and pSMAD2L in alveolar epithelial cells type 2 from tumour-free lung tissue as well as in benign and malignant T cells by Western blotting. Furthermore, pSMAD2L-positive tumours and immune cells were analysed in an NSCLC patient cohort (n = 316) using multiplex immunofluorescence. In NSCLC cell lines and benign T cells, pSMAD2L was expressed in a mitosis-dependent manner. Loss of pSMAD2L (A549Lsub) had an anti-proliferative effect, slowed migration, and increased alternatively spliced short SMAD2 (SMAD2ΔE3). The gene signature in A549Lsub was associated with developmental and morphogenetic processes and redirected canonical TGFβ1-dependent signalling. By contrast, SMAD2ΔE3 was absent in benign T cells but present in malignant T lymphoblasts. NSCLC patients with low pSMAD2L+ tumour cell density had a poorer prognosis, whereas low pSMAD2L+ immune cell density favoured overall and disease-free survival. pSMAD2L antagonises anti-proliferative canonical TGFβ-signalling in NSCLC and redirects TGFβ1-dependent gene expression, whereas loss of pSMAD2L enhances SMAD2ΔE3 and affects pluripotency-associated proteins in vitro. In NSCLC patients, pSMAD2L cell density influences disease-free and overall survival in a spatially distinct manner.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"133 1","pages":"52-65"},"PeriodicalIF":6.4,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-025-02970-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963037","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":"Parity, breastfeeding, and the risk of early-onset breast cancer in women with a BRCA1 pathogenic variant","authors":"Joanne Kotsopoulos, Christopher A. Maxwell, Jan Lubinski, Tomasz Huzarski, Raymond H. Kim, Nadine Tung, Andrea Eisen, William Foulkes, Amber Aeilts, Susan L. Neuhausen, Louise Bordeleau, Rama Khokha, Tuya Pal, Beth Karlan, Robert Fruscio, Fergus Couch, Ping Sun, Jacek Gronwald, Steven A. Narod, on behalf of the Hereditary Breast Cancer Clinical Study Group","doi":"10.1038/s41416-025-03029-x","DOIUrl":"10.1038/s41416-025-03029-x","url":null,"abstract":"It is not clear if breastfeeding and/or parity are associated with the risk of breast cancer among women with a germline pathogenic variant in BRCA1. We sought to evaluate the associations of these two factors with early-onset breast cancer in the BRCA1 pathogenic variant. This case-control study included individuals with a BRCA1 pathogenic variant enroled in a longitudinal study using reproductive and disease histories ascertained at the time of enrolment. Cases had invasive breast cancer prior to age 45, and controls had no breast cancer prior to age 45. Logistic regression was used to evaluate the associations of parity and breastfeeding with cancer risk. Parity per se was not associated with breast cancer risk (OR = 1.09; 95%CI 0.95–1.25); however, among women who never breastfed, the OR for parous vs. nulliparous women was 1.45 (95%CI 1.20–1.75). After matching for parity, ever breastfeeding was associated with 25% lower odds of breast cancer (95%CI 0.61–0.91), and the odds ratio was 0.53 (95%CI 0.40–0.72) for those who breastfed for 20 or more months. Our findings suggest a potential role for breastfeeding in the prevention of young-onset breast cancer among individuals with a BRCA1 pathogenic variant and provide insight into possible prevention targets.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"133 1","pages":"104-110"},"PeriodicalIF":6.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976825","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":"Benzaldehyde suppresses epithelial-mesenchymal plasticity and overcomes treatment resistance in cancer by targeting the interaction of 14-3-3ζ with H3S28ph","authors":"Jun Saito, Nobuyuki Onishi, Juntaro Yamasaki, Naoyoshi Koike, Yukie Hata, Kiyomi Kimura, Yuji Otsuki, Hiroyuki Nobusue, Oltea Sampetrean, Takatsune Shimizu, Shogo Okazaki, Eiji Sugihara, Hideyuki Saya","doi":"10.1038/s41416-025-03006-4","DOIUrl":"10.1038/s41416-025-03006-4","url":null,"abstract":"Benzaldehyde (BA) is an aromatic aldehyde found in fruits that has been studied as a potential anticancer agent on the basis of its ability to inhibit transformation in mouse embryo cells and to suppress metastasis in mice. We investigated the cytotoxic effects of BA on cancer cells, and probed its effects on intracellular signaling pathways. The anticancer effects of BA in vivo were studied by using a mouse orthotopic transplantation model of pancreatic cancer. BA inhibited the growth of osimertinib- or radiation-resistant cancer cells as well as the interaction between 14-3-3ζ and its client proteins. The interaction of 14-3-3ζ with the Ser28-phosphorylated form of histone H3 (H3S28ph) was implicated in treatment resistance and the transcriptional regulation of genes related to epithelial-mesenchymal transition and stemness, including E2F2, SRSF1, and ID1. Treatment of mice with a BA derivative inhibited pancreatic tumor growth and lung metastasis, as well as suppressed a state of epithelial-mesenchymal plasticity (EMP) of tumor cells. The interaction between 14-3-3ζ and H3S28ph plays a key role in EMP and treatment resistance in cancer. The ability of BA to inhibit this and other interactions of 14-3-3ζ offers the potential to overcome treatment resistance and to suppress metastasis.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"133 1","pages":"27-39"},"PeriodicalIF":6.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-025-03006-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964459","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":"Macrophages suppress CD8 + T cell cytotoxic function in triple negative breast cancer via VISTA","authors":"Maidinaimu Abudula, Yuliana Astuti, Meirion Raymant, Vijay Sharma, Michael C. Schmid, Ainhoa Mielgo","doi":"10.1038/s41416-025-03013-5","DOIUrl":"10.1038/s41416-025-03013-5","url":null,"abstract":"Immunotherapy targeting negative immune checkpoint regulators to enhance the anti-tumour immune response holds promise in the treatment of TNBC. V-domain Ig suppressor of T-cell activation (VISTA) is an immune checkpoint molecule, known to be upregulated and involved in modulating tumour immunity in TNBC. However, how VISTA affects immune response and its therapeutic potential in TNBC remains unclear. Here, we examined VISTA expression and cellular distribution in TNBC patients’ samples and pre-clinical TNBC mouse model. Functional assays were performed to assess the impact of VISTA blockade on macrophage phenotypes, CD8 + T cell infiltration and activation, and overall anti-tumour immune response. In this study we show that VISTA expression levels are increased in TNBC patients’ samples and pre-clinical mouse models compared to non-involved breast tissue and VISTA is mainly expressed on tumour infiltrating macrophages and neutrophils. Blocking VISTA reverts macrophages immunosuppressive phenotypes, increases CD8 + T cell infiltration and activation, and enhances an anti-tumour immune response. Mechanistically, we show that neutralising VISTA on macrophages enhances their immune-stimulatory functions and inhibits the suppressive effect of macrophages on CD8 + T cells activation. These findings provide the rationale for the development of anti-VISTA targeting strategies in the treatment of TNBC.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"133 1","pages":"40-51"},"PeriodicalIF":6.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-025-03013-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966659","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":"Retraction Note: Overexpression of HMGA1 promotes anoikis resistance and constitutive Akt activation in pancreatic adenocarcinoma cells","authors":"S-S Liau, A Jazag, K Ito, E E Whang","doi":"10.1038/s41416-025-03036-y","DOIUrl":"10.1038/s41416-025-03036-y","url":null,"abstract":"","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 12","pages":"1200-1200"},"PeriodicalIF":6.4,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-025-03036-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976870","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":"Retraction Note: Glyoxalase I inhibition induces apoptosis in irradiated MCF-7 cells via a novel mechanism involving Hsp27, p53 and NF-κB","authors":"C Antognelli, I Palumbo, C Aristei, V N Talesa","doi":"10.1038/s41416-025-03042-0","DOIUrl":"10.1038/s41416-025-03042-0","url":null,"abstract":"","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 11","pages":"1084-1084"},"PeriodicalIF":6.4,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-025-03042-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966309","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":"Blood metabolic biomarkers and colorectal cancer risk: results from large prospective cohort and Mendelian randomisation analyses","authors":"Fangcheng Yuan, Guochong Jia, Wanqing Wen, Shuai Xu, Valerie Gunchick, Kui Deng, Jirong Long, Danxia Yu, Xiao-Ou Shu, Wei Zheng","doi":"10.1038/s41416-025-02997-4","DOIUrl":"10.1038/s41416-025-02997-4","url":null,"abstract":"Emerging evidence suggests metabolic dysregulation may contribute to colorectal cancer (CRC) aetiology. We aimed to identify pre-diagnostic metabolic biomarkers for CRC risk in 230,420 UK Biobank participants. Nuclear magnetic resonance spectroscopy was used to quantify 249 metabolic biomarkers in plasma samples collected at baseline. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals (CIs) for associations of metabolic biomarkers with CRC risk after adjusting for potential confounders. To infer the potential causality of biomarkers that were associated with CRC independent of the others, we performed genome-wide association analyses among 199,732 UK Biobank participants of European ancestry to identify biomarker-associated genetic variants, followed by two-sample Mendelian randomization (MR) analyses using summary statistics of 78,473 CRC cases and 107,143 controls of European ancestry. During a median follow-up time of 9.7 years, 2,410 incident primary CRC cases were identified. Among 43 CRC-associated (P-value < 0.001) metabolic biomarkers, ten biomarkers including fatty acids (FAs), inflammation, ketone bodies, and lipoprotein lipids were associated with CRC risk after mutual adjustment. MR analyses provided strong evidence for potential causal associations of CRC risk with percentages of linolic acid [odds ratio (OR) = 0.89, 95% CI = 0.83-0.96, P-value = 3 × 10-3] and saturated FAs (OR = 1.14, 95% CI = 1.03–1.25, P-value = 9  ×  10-3) to total FAs. We identified multiple CRC-associated metabolic biomarkers. Perturbed lipid and lipoprotein metabolism may promote colorectal carcinogenesis.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"133 1","pages":"94-103"},"PeriodicalIF":6.4,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-025-02997-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954414","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":"Editorial Expression of Concern: Upregulation of p27 and its inhibition of CDK2/cyclin E activity following DNA damage by a novel platinum agent are dependent on the expression of p21","authors":"G. He, J. Kuang, Z. Huang, J. Koomen, R. Kobayashi, A. R. Khokhar, Z. H. Siddik","doi":"10.1038/s41416-025-03040-2","DOIUrl":"10.1038/s41416-025-03040-2","url":null,"abstract":"","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"132 11","pages":"1083-1083"},"PeriodicalIF":6.4,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41416-025-03040-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970025","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":"POU6F2 promotes liver metastasis of gastric adenocarcinoma by dual mechanism of transcriptional upregulation of SNAI1 and IGF2/PI3K/AKT signaling-induced conversion of hepatic stellate cells into cancer-associated fibroblasts","authors":"Chunxiao Yang, Zhiqing Gao, Ruiming Tang, Lihuan Zhou, Ping Zhou, Wangpan Shi, Dong Ren, Han Chen, Zhuojun Zhang, Xiaoyi Xie, Jiaqian Lin, Yingming Ye, Zhengfu Feng, Xiaoli Feng, Yaoming He, Yaofeng Zhi, Dongmei Liu, Xin Zhang, Lili Jiang","doi":"10.1038/s41416-025-03017-1","DOIUrl":"10.1038/s41416-025-03017-1","url":null,"abstract":"Activation of cancer-associated fibroblasts (CAFs) plays an important role in tumor metastasis. The purpose of this study is to investigate the role of POU6F2 in conversion of hepatic stellate cells (HSCs) into CAFs in liver metastasis of gastric adenocarcinoma (GAC). POU6F2 expression was examined by real-time PCR, Western blot and immunohistochemical staining. The functional roles of POU6F2 in GAC liver metastasis were investigated both cellular experiments in vitro and in vivo using a mouse model of subcutaneous splenic injection. ChIP and ELISA assays were used to explore the underlying molecular mechanism of POU6F2 in liver metastasis of GAC. Here we reported that POU6F2 was upregulated in GAC tissue with liver metastasis, which predicted poor early liver metastasis. Upregulating POU6F2 promoted EMT, invasion and migration of GAC cells in vitro, and the liver metastasis of GAC cells in vivo. Mechanic investigation further revealed that upregulating POU6F2 promoted the invasion and metastasis of GAC by transcriptional upregulation of EMT-inducer SNAI1, and promoting the conversion of HSCs into CAFs dependent on transcriptional upregulation of IGF2-induced activation of PI3K/AKT signaling. Our findings uncover a novel dual mechanism by which POU6F2 promotes liver metastasis of GAC.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"133 1","pages":"14-26"},"PeriodicalIF":6.4,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976869","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":"Rechallenge of ipilimumab and nivolumab in advanced melanoma patients after previous ipilimumab-based therapy","authors":"E. J. van Dijk, H. H. Nienhuis, A. J. M. van den Eertwegh, M. J. Boers-Sonderen, M. Bloem, A. M. Kamphuis, M. M. Ros, C. Bos, M. J. B. Aarts, F. W. P. J. van den Berkmortel, C. U. Blank, W. A. M. Blokx, J. W. B. de Groot, G. A. P. Hospers, D. Piersma, R. S. van Rijn, A. M. Stevense-den Boer, G. Vreugdenhil, M. W. J. M. Wouters, E. Kapiteijn, J. B. Haanen, A. A. M. van der Veldt, K. P. M. Suijkerbuijk","doi":"10.1038/s41416-025-03027-z","DOIUrl":"10.1038/s41416-025-03027-z","url":null,"abstract":"Ipilimumab+nivolumab (IPINIVO) can induce durable responses in advanced melanoma, but many patients experience progression at some point. It is currently unknown to what extent these patients benefit from IPINIVO rechallenge. This study describes efficacy and safety of IPINIVO rechallenge. Data from advanced melanoma patients rechallenged with IPINIVO after previous ipilimumab-containing treatment were retrieved from the nationwide Dutch Melanoma Treatment Registry. Patient characteristics, responses, survival, and safety were analyzed. Among 3.759 patients receiving ipilimumab-containing treatment, 73 received rechallenge IPINIVO. 41 received IPINIVO, 32 ipilimumab monotherapy (IPI) as initial therapy. Objective response to rechallenge IPINIVO was seen in 36.1% (initial IPINIVO) and 40.0% (initial IPI) of patients. Median progression-free survival after rechallenge was 2.8 months (initial IPINIVO) and 5.6 months (initial IPI), but reached 18.4 months for responders to rechallenge therapy. Grade ≥3 immune-related adverse events occurred in 40.5% (initial IPINIVO) and 38.7% (initial IPI) of patients. Objective responses to initial and rechallenge treatment were discordant in 48.6% (initial IPINIVO) and 53.3% (initial IPI) of patients. Fifteen patients (20.5%) responded to rechallenge therapy but not to initial treatment. Rechallenge IPINIVO after previous ipilimumab-based therapy had a considerable response rate, acceptable safety profile, and potential for a durable response.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"133 1","pages":"66-75"},"PeriodicalIF":6.4,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974083","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}