Pub Date : 2025-12-15DOI: 10.1038/s41416-025-03292-y
Kinjal Gupta, Nicholas Koelsch, Victoria Neely, Laura Graham, Harry D. Bear, Michael O. Idowu, Hisashi Harada, Masoud H. Manjili
Chemotherapy-induced tumor dormancy is a major barrier to curative cancer therapy, particularly in triple-negative breast cancer (TNBC), where dormant residual cells evade treatment and fuel late relapses. To define survival mechanisms sustaining dormancy, we examined four breast cancer models: HER2-positive murine MMC and human SK-BR-3, and TNBC murine 4T1 and human MDA-MB-231. Dormancy was induced with low-dose FAC (5-Fluorouracil, Adriamycin, Cyclophosphamide). Across all models, dormant cells maintained high Bcl-xL expression. shRNA knockdown of Bcl-xL increased chemotherapy-induced apoptosis and prevented relapse in vitro and in vivo. Pharmacologic inhibition with A-1331852 improved chemotherapy, particularly in TNBC, and transient dosing avoided compensatory Survivin induction. Systemic A-1331852 suppressed relapse but caused off-target toxicity, whereas intratumoral delivery preserved efficacy and safety but failed to eliminate early lung dissemination, as confirmed by ex vivo culture of dormant tumor cells. Notably, disseminated cell frequency inversely correlated with primary tumor size during neoadjuvant chemotherapy, underscoring the need for systemic therapies targeting distant dormant cells. These findings identify Bcl-xL as a central survival factor in chemotherapy-induced dormancy, and suggest that tumor-targeted systemic delivery of A-1331852 may eradicate disseminated dormant cells and prevent metastatic relapse in high-risk TNBC.
{"title":"Targeting Bcl-xL to eliminate chemotherapy-induced tumor dormancy and prevent breast cancer metastasis","authors":"Kinjal Gupta, Nicholas Koelsch, Victoria Neely, Laura Graham, Harry D. Bear, Michael O. Idowu, Hisashi Harada, Masoud H. Manjili","doi":"10.1038/s41416-025-03292-y","DOIUrl":"10.1038/s41416-025-03292-y","url":null,"abstract":"Chemotherapy-induced tumor dormancy is a major barrier to curative cancer therapy, particularly in triple-negative breast cancer (TNBC), where dormant residual cells evade treatment and fuel late relapses. To define survival mechanisms sustaining dormancy, we examined four breast cancer models: HER2-positive murine MMC and human SK-BR-3, and TNBC murine 4T1 and human MDA-MB-231. Dormancy was induced with low-dose FAC (5-Fluorouracil, Adriamycin, Cyclophosphamide). Across all models, dormant cells maintained high Bcl-xL expression. shRNA knockdown of Bcl-xL increased chemotherapy-induced apoptosis and prevented relapse in vitro and in vivo. Pharmacologic inhibition with A-1331852 improved chemotherapy, particularly in TNBC, and transient dosing avoided compensatory Survivin induction. Systemic A-1331852 suppressed relapse but caused off-target toxicity, whereas intratumoral delivery preserved efficacy and safety but failed to eliminate early lung dissemination, as confirmed by ex vivo culture of dormant tumor cells. Notably, disseminated cell frequency inversely correlated with primary tumor size during neoadjuvant chemotherapy, underscoring the need for systemic therapies targeting distant dormant cells. These findings identify Bcl-xL as a central survival factor in chemotherapy-induced dormancy, and suggest that tumor-targeted systemic delivery of A-1331852 may eradicate disseminated dormant cells and prevent metastatic relapse in high-risk TNBC.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 4","pages":"676-684"},"PeriodicalIF":6.8,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03292-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762168","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}
Pub Date : 2025-12-15DOI: 10.1038/s41416-025-03284-y
Rui Dong, Akshaya Srikanth, Umesh Tharehalli, Thomas Seufferlein, Reinhold Schirmbeck, André Lechel
Hepatocellular carcinoma (HCC) often arises from chronic liver disease, but early biomarkers of malignant transformation are lacking. CD44, a transmembrane glycoprotein with multiple isoforms, has been implicated in cancer progression and immune modulation. We analysed CD44 expression in mouse models of chronic and acute liver injury and assessed its clinical relevance in human HCC using bulk and single-cell transcriptomic datasets. CD44 and its isoforms v6 and v10 were progressively upregulated in chronic liver injury, peaking in HCC. CD44-positive hepatocytes increased with fibrosis severity and were abundant in murine liver tumours. In human HCC, CD44 expression was significantly elevated compared to non-tumorous liver and was associated with reduced overall survival. CD44high tumours showed enrichment in oncogenic signalling pathways and greater infiltration of immunosuppressive cells, including M2 macrophages and Th2 cells. Single-cell RNA-seq confirmed CD44 expression in both tumour and immune cells, linking it to a protumor immune microenvironment. CD44 is a promising early biomarker of hepatocarcinogenesis and a potential therapeutic target. Its expression reflects disease progression from fibrosis to cancer and is associated with poor prognosis and immune evasion in HCC.
{"title":"CD44 upregulation in chronic liver disease marks the transition to hepatocellular carcinoma and portends poor prognosis","authors":"Rui Dong, Akshaya Srikanth, Umesh Tharehalli, Thomas Seufferlein, Reinhold Schirmbeck, André Lechel","doi":"10.1038/s41416-025-03284-y","DOIUrl":"10.1038/s41416-025-03284-y","url":null,"abstract":"Hepatocellular carcinoma (HCC) often arises from chronic liver disease, but early biomarkers of malignant transformation are lacking. CD44, a transmembrane glycoprotein with multiple isoforms, has been implicated in cancer progression and immune modulation. We analysed CD44 expression in mouse models of chronic and acute liver injury and assessed its clinical relevance in human HCC using bulk and single-cell transcriptomic datasets. CD44 and its isoforms v6 and v10 were progressively upregulated in chronic liver injury, peaking in HCC. CD44-positive hepatocytes increased with fibrosis severity and were abundant in murine liver tumours. In human HCC, CD44 expression was significantly elevated compared to non-tumorous liver and was associated with reduced overall survival. CD44high tumours showed enrichment in oncogenic signalling pathways and greater infiltration of immunosuppressive cells, including M2 macrophages and Th2 cells. Single-cell RNA-seq confirmed CD44 expression in both tumour and immune cells, linking it to a protumor immune microenvironment. CD44 is a promising early biomarker of hepatocarcinogenesis and a potential therapeutic target. Its expression reflects disease progression from fibrosis to cancer and is associated with poor prognosis and immune evasion in HCC.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 4","pages":"555-566"},"PeriodicalIF":6.8,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03284-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762191","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}
Pub Date : 2025-12-15DOI: 10.1038/s41416-025-03285-x
Shui-Qing He, Ying Huang, Ze-Yu Zhao, Si-Qing Wen, Shu-Hui Lv, Lin Wang, Wei-Xin Bei, Yan-Qun Xiang, Guo-Ying Liu
We evaluated the clinical impact of combining capecitabine with immunotherapy (Immu/Cape) compared to immunotherapy monotherapy (Immu) as maintenance in recurrent/metastatic (R/M) nasopharyngeal carcinoma (NPC) patients following initial chemo-immunotherapy. We retrospectively analyzed 257 R/M NPC patients who achieved disease control after chemo-immunotherapy and received either Immu/Cape or Immu maintenance. Propensity score matching (PSM) was performed to balance baseline characteristics. Endpoints included progression-free survival (PFS) and overall survival (OS). Following PSM, the Immu/Cape group exhibited prolonged PFS (median, 27.87 vs 8.5 months, p = 0.016) and OS (3-year rate, 80.8% vs. 65.4%; p = 0.027). This survival benefit was most pronounced in patients with high-burden disease: >5 metastatic lesions, ≥2 involved organs, or detectable post-treatment EBV DNA. The primary toxicity was hand-foot syndrome, with a higher incidence in the Immu/Cape group (53.7% vs. 9.8%; p < 0.001), including 12.2% grade 3–4 events; other severe adverse events were comparable. This study provides hypothesis-generating evidence that Immu/Cape maintenance may improve survival in R/M NPC, especially for high-risk patients. Prospective, randomized trials are required to validate this strategy before it can be considered practice-changing.
背景：我们评估了卡培他滨联合免疫治疗（immune /Cape）与免疫治疗单药（immune）作为复发/转移（R/M）鼻咽癌（NPC）患者初始化疗免疫治疗后维持治疗的临床影响。方法：我们回顾性分析257例在化疗免疫治疗后病情得到控制并接受免疫/Cape或免疫维持治疗的R/M鼻咽癌患者。采用倾向评分匹配（PSM）来平衡基线特征。终点包括无进展生存期（PFS）和总生存期（OS）。结果：PSM后，免疫/Cape组PFS延长（中位，27.87 vs 8.5个月，p = 0.016）， OS延长（3年，80.8% vs 65.4%, p = 0.027）。这种生存获益在高负担疾病患者中最为明显：bbb50转移灶，≥2受累器官，或治疗后可检测到EBV DNA。主要毒性为手足综合征，在免疫/Cape组发生率更高（53.7% vs. 9.8%）。结论：本研究提供了假设生成证据，表明维持免疫/Cape可提高R/M鼻咽癌患者的生存率，特别是对高危患者。在考虑改变实践之前，需要前瞻性随机试验来验证该策略。
{"title":"Capecitabine combined with immunotherapy as maintenance therapy improves survival in recurrent/metastatic nasopharyngeal carcinoma: a retrospective cohort study","authors":"Shui-Qing He, Ying Huang, Ze-Yu Zhao, Si-Qing Wen, Shu-Hui Lv, Lin Wang, Wei-Xin Bei, Yan-Qun Xiang, Guo-Ying Liu","doi":"10.1038/s41416-025-03285-x","DOIUrl":"10.1038/s41416-025-03285-x","url":null,"abstract":"We evaluated the clinical impact of combining capecitabine with immunotherapy (Immu/Cape) compared to immunotherapy monotherapy (Immu) as maintenance in recurrent/metastatic (R/M) nasopharyngeal carcinoma (NPC) patients following initial chemo-immunotherapy. We retrospectively analyzed 257 R/M NPC patients who achieved disease control after chemo-immunotherapy and received either Immu/Cape or Immu maintenance. Propensity score matching (PSM) was performed to balance baseline characteristics. Endpoints included progression-free survival (PFS) and overall survival (OS). Following PSM, the Immu/Cape group exhibited prolonged PFS (median, 27.87 vs 8.5 months, p = 0.016) and OS (3-year rate, 80.8% vs. 65.4%; p = 0.027). This survival benefit was most pronounced in patients with high-burden disease: >5 metastatic lesions, ≥2 involved organs, or detectable post-treatment EBV DNA. The primary toxicity was hand-foot syndrome, with a higher incidence in the Immu/Cape group (53.7% vs. 9.8%; p < 0.001), including 12.2% grade 3–4 events; other severe adverse events were comparable. This study provides hypothesis-generating evidence that Immu/Cape maintenance may improve survival in R/M NPC, especially for high-risk patients. Prospective, randomized trials are required to validate this strategy before it can be considered practice-changing.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 4","pages":"598-607"},"PeriodicalIF":6.8,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03285-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762179","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}
Pub Date : 2025-12-13DOI: 10.1038/s41416-025-03276-y
Büsra Ernhofer, Anna Solta, Julia Sinner, Zsolt Megyesfalvi, Abigail J. Deloria, Kristiina Boettiger, Lisa Glatt, Lilla Horvath, Caterina Sturtzel, Andrea Wenninger-Weinzierl, Martin Distel, Michael Grusch, Beata Szeitz, Melinda Rezeli, Clemens Aigner, Balazs Dome, Karin Schelch
Early metastatic spread represents a challenge in fighting small cell lung cancer (SCLC). The molecular mechanisms underlying metastatic dissemination remain unclear in this devastating disease. Invasive traits were investigated in 13 SCLC cell lines using 3D-spheroid formation, sprouting assays, co-cultures and a zebrafish xenograft model. Proteomic analysis was performed to unravel metastatic drivers, which were validated by qPCR, growth factor arrays and specific inhibitors. Overall, 8 cell lines formed spheroids, and half of these displayed invasive sprouting in collagen. The ‘sprouter’ SCLC cells, which all had a YAP1-dominant subtype, showed increased migration in zebrafish larvae and penetrated endothelial cell monolayers to a higher extent, thereby mimicking intra- and extravasation. Proteomics revealed differences in adhesion properties, oncogenic pathways and receptor tyrosine kinase signalling. Sprouter cells showed higher expression levels of mesenchymal cell state markers. Stimulation with fibroblast growth factor 2 (FGF2) further induced invasive sprouting, while blocking the FGF/R axis resulted in a significant reduction of sprouting in vitro and in vivo. The FGF/R axis is a key driver of SCLC metastatic spread in the YAP1-dominant subtype. These data might facilitate the development of potential future therapies targeting FGF/R signalling to prevent SCLC progression and metastasis.
{"title":"Fibroblast growth factor signals drive the metastatic behavior in small cell lung cancer","authors":"Büsra Ernhofer, Anna Solta, Julia Sinner, Zsolt Megyesfalvi, Abigail J. Deloria, Kristiina Boettiger, Lisa Glatt, Lilla Horvath, Caterina Sturtzel, Andrea Wenninger-Weinzierl, Martin Distel, Michael Grusch, Beata Szeitz, Melinda Rezeli, Clemens Aigner, Balazs Dome, Karin Schelch","doi":"10.1038/s41416-025-03276-y","DOIUrl":"10.1038/s41416-025-03276-y","url":null,"abstract":"Early metastatic spread represents a challenge in fighting small cell lung cancer (SCLC). The molecular mechanisms underlying metastatic dissemination remain unclear in this devastating disease. Invasive traits were investigated in 13 SCLC cell lines using 3D-spheroid formation, sprouting assays, co-cultures and a zebrafish xenograft model. Proteomic analysis was performed to unravel metastatic drivers, which were validated by qPCR, growth factor arrays and specific inhibitors. Overall, 8 cell lines formed spheroids, and half of these displayed invasive sprouting in collagen. The ‘sprouter’ SCLC cells, which all had a YAP1-dominant subtype, showed increased migration in zebrafish larvae and penetrated endothelial cell monolayers to a higher extent, thereby mimicking intra- and extravasation. Proteomics revealed differences in adhesion properties, oncogenic pathways and receptor tyrosine kinase signalling. Sprouter cells showed higher expression levels of mesenchymal cell state markers. Stimulation with fibroblast growth factor 2 (FGF2) further induced invasive sprouting, while blocking the FGF/R axis resulted in a significant reduction of sprouting in vitro and in vivo. The FGF/R axis is a key driver of SCLC metastatic spread in the YAP1-dominant subtype. These data might facilitate the development of potential future therapies targeting FGF/R signalling to prevent SCLC progression and metastasis.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 4","pages":"543-554"},"PeriodicalIF":6.8,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03276-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145751662","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}
Pub Date : 2025-12-11DOI: 10.1038/s41416-025-03300-1
Ville K. Äijälä, Jouni Härkönen, Päivi Sirniö, Tuomo Mantere, Hanna Elomaa, Onni Sirkiä, Akseli Kehusmaa, Henna Karjalainen, Meeri Kastinen, Vilja V. Tapiainen, Maarit Ahtiainen, Olli Helminen, Erkki-Ville Wirta, Jukka Rintala, Sanna Meriläinen, Juha Saarnio, Tero Rautio, Toni T. Seppälä, Jan Böhm, Jukka-Pekka Mecklin, Anne Tuomisto, Markus J. Mäkinen, Juha P. Väyrynen
Uroplakin-2 (UPK2) is a relatively specific marker for urothelial cancer, often used in the differential diagnosis of tumors of unknown origin. UPK2 expression has been observed in colorectal cancers (CRCs), prompting further investigation. UPK2 expression was analyzed in two independent CRC cohorts (N = 1851) and The Cancer Genome Atlas (N = 467). We investigated the histopathological, immunological, molecular, and clinical characteristics of UPK2-positive CRCs. UPK2 was expressed in 12% of CRCs and associated with adverse features including advanced stage, lymphovascular invasion, tumor budding, and micropapillary growth (p < 0.01). UPK2 positivity correlated with higher CRC-specific mortality in both cohorts (Cohort 1: HR 1.97, 95% CI 1.00–3.88; Cohort 2: HR 3.33, 95% CI 2.15–5.16). In the larger cohort, this association remained independent of other prognostic parameters (HR 2.31, 95% CI 1.46–3.65). UPK2-positive tumors showed reduced infiltration of CD3 + T cells, B cells, plasma cells, and M2-like macrophages. Molecularly, these tumors were associated with TP53 mutation, CMS4 subtype, and upregulation of genes linked to keratinization and squamous differentiation, such as KRT17 and DSG3 (p < 0.01). UPK2 marks a distinct subset of CRCs with poor prognosis, epithelial-mesenchymal transition, micropapillary growth, and squamous differentiation. These findings may affect the development of targeted therapies in precision medicine.
{"title":"Urothelium marker UPK2 identifies aggressive colorectal cancers with distinct molecular and histological features","authors":"Ville K. Äijälä, Jouni Härkönen, Päivi Sirniö, Tuomo Mantere, Hanna Elomaa, Onni Sirkiä, Akseli Kehusmaa, Henna Karjalainen, Meeri Kastinen, Vilja V. Tapiainen, Maarit Ahtiainen, Olli Helminen, Erkki-Ville Wirta, Jukka Rintala, Sanna Meriläinen, Juha Saarnio, Tero Rautio, Toni T. Seppälä, Jan Böhm, Jukka-Pekka Mecklin, Anne Tuomisto, Markus J. Mäkinen, Juha P. Väyrynen","doi":"10.1038/s41416-025-03300-1","DOIUrl":"10.1038/s41416-025-03300-1","url":null,"abstract":"Uroplakin-2 (UPK2) is a relatively specific marker for urothelial cancer, often used in the differential diagnosis of tumors of unknown origin. UPK2 expression has been observed in colorectal cancers (CRCs), prompting further investigation. UPK2 expression was analyzed in two independent CRC cohorts (N = 1851) and The Cancer Genome Atlas (N = 467). We investigated the histopathological, immunological, molecular, and clinical characteristics of UPK2-positive CRCs. UPK2 was expressed in 12% of CRCs and associated with adverse features including advanced stage, lymphovascular invasion, tumor budding, and micropapillary growth (p < 0.01). UPK2 positivity correlated with higher CRC-specific mortality in both cohorts (Cohort 1: HR 1.97, 95% CI 1.00–3.88; Cohort 2: HR 3.33, 95% CI 2.15–5.16). In the larger cohort, this association remained independent of other prognostic parameters (HR 2.31, 95% CI 1.46–3.65). UPK2-positive tumors showed reduced infiltration of CD3 + T cells, B cells, plasma cells, and M2-like macrophages. Molecularly, these tumors were associated with TP53 mutation, CMS4 subtype, and upregulation of genes linked to keratinization and squamous differentiation, such as KRT17 and DSG3 (p < 0.01). UPK2 marks a distinct subset of CRCs with poor prognosis, epithelial-mesenchymal transition, micropapillary growth, and squamous differentiation. These findings may affect the development of targeted therapies in precision medicine.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 4","pages":"650-661"},"PeriodicalIF":6.8,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03300-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741160","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}
Pub Date : 2025-12-11DOI: 10.1038/s41416-025-03279-9
Grégoire Berthod, Christophe Cisarovsky, Tatiana Petrova, Laurent A. Decosterd, Eva Choong, Dan Celestini, Michel A. Cuendet, Sarah Boughdad, John O. Prior, Jean-Yves Meuwly, William D. Figg, Olivier Michielin, Serge Leyvraz
Selective internal radiation therapy (SIRT) and sorafenib are used for patients with liver metastases from uveal melanoma. We conducted a phase I study to determine the optimal timing of administration of sorafenib in combination with radioembolisation. Patients received radioembolisation plus sorafenib initiated 14, 11, or 3 days after or 7 days before radioembolisation. The primary endpoint was safety. Secondary endpoints included efficacy and evaluation of circulating angiogenic factors. Sorafenib plasma levels were quantified retrospectively. Ten patients received radioembolisation plus sorafenib. The most common grade 2–4 adverse events included rash, abdominal pain, fatigue and lymphocytopenia. Best response was partial response (30%) and stable disease (70%). Median progression-free and overall survival were 6.2 (4.8–not reached) and 11.7 months (9.4–not reached), respectively. Circulating angiogenic factors showed transient elevation at Day 10 post-SIRT when sorafenib was started 11–14 days after SIRT, but not when sorafenib was started before or just after SIRT. Most steady-state sorafenib plasma concentrations were in the upper percentiles relative to reference curves for single-agent sorafenib. SIRT plus sorafenib was feasible, but appeared more toxic than sorafenib alone, presumably due to altered pharmacokinetics. Sorafenib may hinder the angiogenic response when initiated before or shortly after SIRT. Registry: ClinicalTrials.gov, NCT01893099.
{"title":"Sorafenib plus selective internal radiotherapy with 90Y resin microspheres for the treatment of uveal melanoma with liver metastasis: a phase I trial","authors":"Grégoire Berthod, Christophe Cisarovsky, Tatiana Petrova, Laurent A. Decosterd, Eva Choong, Dan Celestini, Michel A. Cuendet, Sarah Boughdad, John O. Prior, Jean-Yves Meuwly, William D. Figg, Olivier Michielin, Serge Leyvraz","doi":"10.1038/s41416-025-03279-9","DOIUrl":"10.1038/s41416-025-03279-9","url":null,"abstract":"Selective internal radiation therapy (SIRT) and sorafenib are used for patients with liver metastases from uveal melanoma. We conducted a phase I study to determine the optimal timing of administration of sorafenib in combination with radioembolisation. Patients received radioembolisation plus sorafenib initiated 14, 11, or 3 days after or 7 days before radioembolisation. The primary endpoint was safety. Secondary endpoints included efficacy and evaluation of circulating angiogenic factors. Sorafenib plasma levels were quantified retrospectively. Ten patients received radioembolisation plus sorafenib. The most common grade 2–4 adverse events included rash, abdominal pain, fatigue and lymphocytopenia. Best response was partial response (30%) and stable disease (70%). Median progression-free and overall survival were 6.2 (4.8–not reached) and 11.7 months (9.4–not reached), respectively. Circulating angiogenic factors showed transient elevation at Day 10 post-SIRT when sorafenib was started 11–14 days after SIRT, but not when sorafenib was started before or just after SIRT. Most steady-state sorafenib plasma concentrations were in the upper percentiles relative to reference curves for single-agent sorafenib. SIRT plus sorafenib was feasible, but appeared more toxic than sorafenib alone, presumably due to altered pharmacokinetics. Sorafenib may hinder the angiogenic response when initiated before or shortly after SIRT. Registry: ClinicalTrials.gov, NCT01893099.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 4","pages":"589-597"},"PeriodicalIF":6.8,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03279-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741167","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}
Pub Date : 2025-12-10DOI: 10.1038/s41416-025-03280-2
Laura Solé, Eric Canton, María Maqueda, Teresa Lobo-Jarne, Antonio Barbáchano, Ferran Torres, Julia-Jié Cabré-Romans, Ángela Montoto, Lierni Fernández-Ibarrondo, Daniel Martínez-Garcia, Marta Guix, Mónica Larrubia-Loring, Clara Montagut, Alberto Muñoz, Anna Bigas, Mar Iglesias, Beatriz Bellosillo, Lluís Espinosa
We have previously shown that non-curative chemotherapy imposes fetal conversion and high metastatic capacity to cancer cells. Analysis of public colorectal cancer datasets confirms the existence of a oncofetal signature consisting of 28 upregulated and 8 downregulated genes that stratify patients with worse prognosis. We have generated and analyzed a metacohort which integrates 1118 samples from six colorectal cancer public datasets and performed qPCR analysis of paraffin-embedded and plasma samples from our in-house cohort of colorectal cancer tumors. We uncovered a core oncofetal signature, which we have called ColoStem, composed of 5 genes upregulated and 3 genes downregulated that displays prognosis value in a multivariate analysis. We also defined EpiColoStem, a reduction of ColoStem, as a pure epithelial signature with comparable prognosis value as ColoStem. By qPCR analysis of RNA extracted from paraffin-embedded tissues, we demonstrated the actual possibility of using ColoStem and EpiColoStem to refine the prognosis of CRC patients with a simple an affordable method. Initial analysis of plasma samples indicated that both signatures could be adapted for its use in liquid biopsy. Our results reveal ColoStem and EpiColoStem tests as valuable tools for refining patient prognosis through the identification of fetal-type CRC tumors.
{"title":"ColoStem, a core oncofetal signature that identifies poor prognosis colorectal tumors","authors":"Laura Solé, Eric Canton, María Maqueda, Teresa Lobo-Jarne, Antonio Barbáchano, Ferran Torres, Julia-Jié Cabré-Romans, Ángela Montoto, Lierni Fernández-Ibarrondo, Daniel Martínez-Garcia, Marta Guix, Mónica Larrubia-Loring, Clara Montagut, Alberto Muñoz, Anna Bigas, Mar Iglesias, Beatriz Bellosillo, Lluís Espinosa","doi":"10.1038/s41416-025-03280-2","DOIUrl":"10.1038/s41416-025-03280-2","url":null,"abstract":"We have previously shown that non-curative chemotherapy imposes fetal conversion and high metastatic capacity to cancer cells. Analysis of public colorectal cancer datasets confirms the existence of a oncofetal signature consisting of 28 upregulated and 8 downregulated genes that stratify patients with worse prognosis. We have generated and analyzed a metacohort which integrates 1118 samples from six colorectal cancer public datasets and performed qPCR analysis of paraffin-embedded and plasma samples from our in-house cohort of colorectal cancer tumors. We uncovered a core oncofetal signature, which we have called ColoStem, composed of 5 genes upregulated and 3 genes downregulated that displays prognosis value in a multivariate analysis. We also defined EpiColoStem, a reduction of ColoStem, as a pure epithelial signature with comparable prognosis value as ColoStem. By qPCR analysis of RNA extracted from paraffin-embedded tissues, we demonstrated the actual possibility of using ColoStem and EpiColoStem to refine the prognosis of CRC patients with a simple an affordable method. Initial analysis of plasma samples indicated that both signatures could be adapted for its use in liquid biopsy. Our results reveal ColoStem and EpiColoStem tests as valuable tools for refining patient prognosis through the identification of fetal-type CRC tumors.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 4","pages":"638-649"},"PeriodicalIF":6.8,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03280-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721251","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}
Pub Date : 2025-12-10DOI: 10.1038/s41416-025-03283-z
Zhuangjie Guo, Jinkun Chen, Siyu Zhang, Jungang Xie, Hong Zhang, Pinpin Long, Peiran Yang
Lung cancer is highly lethal because most patients have already developed metastases at diagnosis, yet the epigenetic mechanisms driving metastasis are unclear. We performed an epigenome-wide association study on 42 lung cancer patients to identify differentially methylated positions (DMPs) in pulmonary tumour (PT), paratumor (PP), and normal (PN) tissues, and in peripheral blood. The impact of DMPs on gene expression and associated signalling pathways was examined. Functional validation included gene silencing in A549 and H1299 cells, analysis of the affected signalling pathway, and assessment of metastasis using mice injected with genetically edited cells. We identified 22 significant DMPs between PP and PN tissues, with several mapped to the RNLS promoter region, showing progressive hypomethylation from PN, PP, to PT. This hypomethylation was also present in the peripheral blood of patients who later developed metastasis. RNLS methylation was inversely correlated with its expression across multiple tissue types. The DMPs were enriched in Notch signalling. Silencing RNLS inhibited cancer cell proliferation and migration, and downregulated Notch signalling. RNLS deficiency reduced metastatic burden in mice. RNLS hypomethylation is an epigenetic alteration associated with lung cancer metastasis, with potential as an early biomarker and as a therapeutic target.
{"title":"RNLS hypomethylation as a potential epigenetic marker of lung cancer metastasis: an epigenome-wide association study","authors":"Zhuangjie Guo, Jinkun Chen, Siyu Zhang, Jungang Xie, Hong Zhang, Pinpin Long, Peiran Yang","doi":"10.1038/s41416-025-03283-z","DOIUrl":"10.1038/s41416-025-03283-z","url":null,"abstract":"Lung cancer is highly lethal because most patients have already developed metastases at diagnosis, yet the epigenetic mechanisms driving metastasis are unclear. We performed an epigenome-wide association study on 42 lung cancer patients to identify differentially methylated positions (DMPs) in pulmonary tumour (PT), paratumor (PP), and normal (PN) tissues, and in peripheral blood. The impact of DMPs on gene expression and associated signalling pathways was examined. Functional validation included gene silencing in A549 and H1299 cells, analysis of the affected signalling pathway, and assessment of metastasis using mice injected with genetically edited cells. We identified 22 significant DMPs between PP and PN tissues, with several mapped to the RNLS promoter region, showing progressive hypomethylation from PN, PP, to PT. This hypomethylation was also present in the peripheral blood of patients who later developed metastasis. RNLS methylation was inversely correlated with its expression across multiple tissue types. The DMPs were enriched in Notch signalling. Silencing RNLS inhibited cancer cell proliferation and migration, and downregulated Notch signalling. RNLS deficiency reduced metastatic burden in mice. RNLS hypomethylation is an epigenetic alteration associated with lung cancer metastasis, with potential as an early biomarker and as a therapeutic target.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 4","pages":"627-637"},"PeriodicalIF":6.8,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721243","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}
The development of early-onset colorectal cancer (EO-CRC) is linked to environmental exposures and gut microbiota alterations. We aimed to discover the connection and develop prediction strategies. In the observational study, we performed 16S rRNA sequencing and metagenomic sequencing on 76 samples from discovery cohort and validation cohort, and qPCR analysis of selected microbiota, along with lifestyle and dietary assessment on 298 samples from validation cohort. Mediation analysis was employed to investigate the mediating role of gut microbiota. Logistic regression analysis evaluated the optimal prediction model for EO-CRC, with the area under the receiver operating characteristic curves (AUC) assessing diagnostic value. Dysbiosis of the EO-CRC gut microbiota was characterised by evaluated abundance of F. nucleatum, P. micra, Pks+ E. coli, and F. Plautii. Mediation analysis showed that Pks+ E. coli mediated the relationship between fried food, processed meat and coffee to EO-CRC, while F. nucleatum mediated the adverse effects of snacks. A combination of three bacterial markers along with lifestyle and diet demonstrated strong diagnostic potential (AUC = 0.95, 95% CI = 0.92–0.98). Our data suggested that the EO-CRC-enriched bacteria may mediate the effects of lifestyle and dietary factors on disease development. A predictive model combining diet, lifestyle, and gut bacteria demonstrated promising early predictive capabilities.
{"title":"The relationship between gut microbiota, lifestyle habits, and early-onset colorectal cancer: shedding light on early prediction","authors":"Jia-Wen Deng, Yi-Lu Zhou, Ya-Xuan Zhang, Cheng-Bei Zhou, Jing-Yuan Fang","doi":"10.1038/s41416-025-03277-x","DOIUrl":"10.1038/s41416-025-03277-x","url":null,"abstract":"The development of early-onset colorectal cancer (EO-CRC) is linked to environmental exposures and gut microbiota alterations. We aimed to discover the connection and develop prediction strategies. In the observational study, we performed 16S rRNA sequencing and metagenomic sequencing on 76 samples from discovery cohort and validation cohort, and qPCR analysis of selected microbiota, along with lifestyle and dietary assessment on 298 samples from validation cohort. Mediation analysis was employed to investigate the mediating role of gut microbiota. Logistic regression analysis evaluated the optimal prediction model for EO-CRC, with the area under the receiver operating characteristic curves (AUC) assessing diagnostic value. Dysbiosis of the EO-CRC gut microbiota was characterised by evaluated abundance of F. nucleatum, P. micra, Pks+ E. coli, and F. Plautii. Mediation analysis showed that Pks+ E. coli mediated the relationship between fried food, processed meat and coffee to EO-CRC, while F. nucleatum mediated the adverse effects of snacks. A combination of three bacterial markers along with lifestyle and diet demonstrated strong diagnostic potential (AUC = 0.95, 95% CI = 0.92–0.98). Our data suggested that the EO-CRC-enriched bacteria may mediate the effects of lifestyle and dietary factors on disease development. A predictive model combining diet, lifestyle, and gut bacteria demonstrated promising early predictive capabilities.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 3","pages":"469-476"},"PeriodicalIF":6.8,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145713278","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}
Pub Date : 2025-12-09DOI: 10.1038/s41416-025-03259-z
Sarah J. Bowden, Laura Burney Ellis, Tamzin Cuming, Danielle Brogden, Susan M. Sherman, David A. Finch, Shaun Haran, Julie Bowring, George Mochloulis, Alice M. Schofield, Archie Krishna, Andrew G. Renehan, Maggie E. Cruickshank, Pierre Martin-Hirsch, Maria Kyrgiou, Deirdre Lyons, Theresa Freeman-Wang
Multizonal anogenital intraepithelial neoplasia (MZIN) is an uncommon chronic pre-malignant condition. In the United Kingdom (UK) and elsewhere MZIN is managed by a variety of clinical specialities with differing strategies, resulting in a lack of standardisation in diagnosis and treatment which ultimately disadvantages those affected. Screening for anogenital precancerous conditions is sporadic rather than nationalised in the UK and elsewhere in Europe, with the exception of the cervix. To address this lack of standardisation, the BSCCP brought together a panel of stakeholders from aligned expert society committees (IANS, EFC and BSSVD) to review existing evidence and provide a framework for national UK guidelines. Here, we define terminology and scope, as a platform for subsequent guideline development and guide further research. We define MZIN as Human Papillomavirus (HPV)-related squamous intraepithelial lesions occurring in two or more anogenital regions. People with MZIN are a high-risk group for anogenital cancers and subsequently may require tailored monitoring in specialist multi-disciplinary clinics. Centralisation of care and education for primary care providers may improve management. The development of guidelines which incorporate all clinical stakeholders are now needed to provide an international framework regarding the screening, diagnosis, treatment and future prevention of MZIN.
{"title":"Multizonal intraepithelial neoplasia of the lower genital tract and anus in women: terminology for defining the disease, an introduction by the British Society for Colposcopy and Cervical Pathology (BSCCP), International Anal Neoplasia Society (IANS), European Federation for Colposcopy (EFC) and British Society for the Study of Vulval Disease (BSSVD) scientific committees","authors":"Sarah J. Bowden, Laura Burney Ellis, Tamzin Cuming, Danielle Brogden, Susan M. Sherman, David A. Finch, Shaun Haran, Julie Bowring, George Mochloulis, Alice M. Schofield, Archie Krishna, Andrew G. Renehan, Maggie E. Cruickshank, Pierre Martin-Hirsch, Maria Kyrgiou, Deirdre Lyons, Theresa Freeman-Wang","doi":"10.1038/s41416-025-03259-z","DOIUrl":"10.1038/s41416-025-03259-z","url":null,"abstract":"Multizonal anogenital intraepithelial neoplasia (MZIN) is an uncommon chronic pre-malignant condition. In the United Kingdom (UK) and elsewhere MZIN is managed by a variety of clinical specialities with differing strategies, resulting in a lack of standardisation in diagnosis and treatment which ultimately disadvantages those affected. Screening for anogenital precancerous conditions is sporadic rather than nationalised in the UK and elsewhere in Europe, with the exception of the cervix. To address this lack of standardisation, the BSCCP brought together a panel of stakeholders from aligned expert society committees (IANS, EFC and BSSVD) to review existing evidence and provide a framework for national UK guidelines. Here, we define terminology and scope, as a platform for subsequent guideline development and guide further research. We define MZIN as Human Papillomavirus (HPV)-related squamous intraepithelial lesions occurring in two or more anogenital regions. People with MZIN are a high-risk group for anogenital cancers and subsequently may require tailored monitoring in specialist multi-disciplinary clinics. Centralisation of care and education for primary care providers may improve management. The development of guidelines which incorporate all clinical stakeholders are now needed to provide an international framework regarding the screening, diagnosis, treatment and future prevention of MZIN.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 2","pages":"177-184"},"PeriodicalIF":6.8,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03259-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145713230","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}
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