Cancer research最新文献

{"title":"SPP1 Drives Colorectal Cancer Liver Metastasis and Immunotherapy Resistance by Stimulating CXCL12 Production in Cancer-Associated Fibroblasts.","authors":"Shengde Liu,Zizhen Zhang,Zhenghang Wang,Cheng Liu,Guanghao Liang,Ting Xu,Zhiwei Li,Xiaorui Duan,Gehan Xu,Xujiao Feng,Qin Feng,Qi Wang,Dali Han,Cheng Zhang,Jian Li,Lin Shen","doi":"10.1158/0008-5472.can-24-4916","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-4916","url":null,"abstract":"Colorectal cancer (CRC) remains a major cause of cancer-related morbidity and mortality globally, with 30%-40% of cases developing metastasis, mainly to the liver. Although immunotherapy has shown promise for CRC treatment, patients with CRC liver metastasis (CRLM) experience limited therapeutic benefits, potentially because of an immunosuppressive tumor microenvironment (TME). Thus, an urgent need exists to identify the key players that drive CRLM and potentiate immunotherapeutic resistance. Herein, we established liver metastatic cells through continuous passaging in vivo, allowing the screening of RNA expression profiles related to CRLM. A combination of spatial transcriptomic sequencing and single-cell analysis revealed a substantial upregulation of SPP1 expression and secretion in CRLM. SPP1 induced immunotherapeutic resistance by stimulating CXCL12 production by cancer-associated fibroblasts (CAFs) through activation of β-catenin/HIF-1α-related transcription. CXCL12 promoted epithelial-mesenchymal transition of CRC cells but suppressed CD8+ T cell infiltration. Treatment with a CXCL12 receptor antagonist or anti-SPP1 antibody markedly activated intratumoral CD8+ T cell infiltration and enhanced the efficacy of anti-PD-1 antibody treatment. Elevated SPP1 and CXCL12 corresponded to immunotherapy resistance in CRLM patients. Together, this study highlights the potential of the SPP1/CXCL12 axis as a target and a biomarker for precise cancer immunotherapy in CRLM. The intricate interactions within the TME offer promising avenues for improving therapeutic outcomes in CRC patients with liver metastasis.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"27 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229104","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":"FLT3-ITD Induces CMTM6 and Enhances Immune Escape in Acute Myeloid Leukemia","authors":"Melissa Zwick, Bastian Zinkel, Corinna Spohr, Tamina Rückert, Sebastian Halbach, Khalid Shoumariyeh, Jonas Scheid, Anna-Sophia Baur, Lukas M. Braun, Moritz Angel, Elisa Michaeli, Abhijeet Todkar, Annika Nelde, Melanie Märklin, Samuel J. Holzmayer, Severin Dicks, Melanie Boerries, Sandra Duquesne, Alexandra Emilia Schlaak, Patricia Otto-Mora, Bertram Bengsch, Marcel Schiff, Sandra Kissel, Michael Selle, Marie Follo, Heidi Altmann, Desiree Kunadt, Anna-Lena Illert, Juliane S. Walz, Gerd Walz, Justus Duyster, Johannes Schetelig, Tilman Brummer, Robert Zeiser, Natalie Köhler","doi":"10.1158/0008-5472.can-25-0349","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0349","url":null,"abstract":"FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutations are frequent in acute myeloid leukemia (AML) and are associated with a high risk of relapse. CKLF-like MARVEL transmembrane domain containing member 6 (CMTM6) stabilizes PD-L1 surface expression and modulates tumor immunity in solid cancer. In this study, we found a role for FLT3-induced CMTM6 in hematological malignancies. FLT3 drove CMTM6 and PD-L1 expression in AML cells, while FLT3 inhibition reduced expression of CMTM6 and PD-L1. In three distinct allogeneic hematopoietic cell transplantation mouse models, transplantation of Cmtm6 deficient FLT3-ITD+ leukemia cells resulted in prolonged survival, reduced leukemia burden, enhanced T cell effector function, and decreased expression of T cell exhaustion markers compared to Cmtm6 proficient FLT3-ITD+ leukemia cells. Furthermore, combination therapy with anti-PD-L1 and tandutinib significantly improved survival, suppressed leukemia cell expansion, and augmented the anti-leukemia T cell response in mice bearing FLT3-ITD+ leukemia. Mechanistically, protein-protein interaction of FLT3 and CMTM6 within their transmembrane domains, which was not phosphorylation dependent, enhanced CMTM6 stability in leukemia cells, while FLT3-ITD did not increase CMTM6 and PD-L1 expression at the RNA level. Furthermore, CMTM6 upregulation and protein interaction with FLT3 was validated in primary leukemia cells from two independent cohorts of patients with FLT3-ITD+ AML. Collectively, these findings uncover FLT3-mediated stabilization of CMTM6 in AML cells, which results in enhanced PD-L1 cell surface expression and leukemia immune escape.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"94 8 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215550","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":"From Worms to Tumors: Conserved Strategies of Cellular Arrest and Survival Governing Dormancy","authors":"Veena Prahlad, Irwin H. Gelman","doi":"10.1158/0008-5472.can-25-2050","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-2050","url":null,"abstract":"The recurrence of metastatic lesions months to years after the treatment of primary cancers remains a major contributor to cancer-related mortality, highlighting the need to better understand the mechanisms that govern dormancy and dormancy reawakening. A major hurdle is the lack of adequate in vitro and in vivo models to dissect the complex cascades that trigger tumor cell dissemination, adoption of the dormant state, or tumor cell outgrowth in the new metastatic microenvironmental niche. However, many organisms use dormancy to survive stressful environments or periods of nutrient deprivation. Of these, the dauer state of the free-living nematodes C. elegans has unparalleled characterization. Here, we discuss the remarkable physiological, signaling, genomic, and metabolic similarities between dormant cancer cells and C. elegans dauers, arguing for the use of dauers as a facile model to help dissect dormancy and reawakening pathways in cancer cells.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"41 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215548","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":"Editor's Note: Werner Syndrome Helicase Has a Critical Role in DNA Damage Responses in the Absence of a Functional Fanconi Anemia Pathway.","authors":"Monika Aggarwal, Taraswi Banerjee, Joshua A Sommers, Chiara Iannascoli, Pietro Pichierri, Robert H Shoemaker, Robert M Brosh","doi":"10.1158/0008-5472.CAN-25-3491","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-25-3491","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"85 19","pages":"3813"},"PeriodicalIF":16.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198519","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":"Generations in Flux: Tracking the Birth of Cellular Heterogeneity in Cancer.","authors":"Aaron McKenna","doi":"10.1158/0008-5472.CAN-25-3601","DOIUrl":"10.1158/0008-5472.CAN-25-3601","url":null,"abstract":"<p><p>Intratumor heterogeneity is a hallmark of cancer, enabling subpopulations of cells to evade therapy, adapt to immune attack, and thrive in diverse microenvironments. Although retrospective genomic and epigenomic analyses have mapped the large-scale histories of tumor evolution, they cannot capture the rapid, dynamic changes in cell state that occur as individual cells divide. Panagopoulos and colleagues recently developed a cellular platform to monitor the role of transient replication stress in real time, tracking sister cells as they divide and replicate. The authors use these techniques to show that daughter and granddaughter cells can inherit very different states, often leading to further cellular instability. This work broadens our understanding of how diverse cell states arise from oncogenic stress and how cellular heterogeneity emerges in cancer.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"3582-3583"},"PeriodicalIF":16.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871619","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":"Targeting SUV4-20H Epigenetic Enzymes Enhances Topoisomerase II Poisoning in Prostate Cancer","authors":"Fatima Alhourani, Marine Tauziet, Margaux Ayeul, Pierre Dambrun, Hiba Daher, Julie Patouillard, Benoit Miotto, Aurélie Gennetier, Simon George, Xavier Mialhe, Mona Dergham, Florence M. Cammas, Adeline Torro, Diego Tosi, Celine Gongora, Philippe Pourquier, Cyril Ribeyre, Véronique Baldin, Raghida Abou Merhi, Eric Julien","doi":"10.1158/0008-5472.can-24-3974","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3974","url":null,"abstract":"Commonly used in cancer therapy, topoisomerase II (TOP2) poisons are designed to stabilize the normally transient DNA TOP2 cleavage complexes in chromatin, leading to deleterious DNA double-strand breaks. TOP2 poisons are often associated with significant side effects, highlighting the need to identify strategies aimed at improving the efficacy of TOP2 poisons in order to lower the required dosage. Here, we demonstrated that inhibiting histone H4-lysine 20 (H4K20) methyltransferases SUV4-20H1 and SUV4-20H2 induced synthetic lethality in combination with the TOP2 poison etoposide in prostate cancer. Remarkably, the loss of the SUV4-20H enzymes, which prevents the conversion of H4K20 mono-methylation to higher methylation states, increased replication fork velocity without impacting prostate cancer cell behavior. However, these apparently innocuous epigenetic changes significantly enhanced the trapping of TOP2 complexes in chromatin and increased DNA damage in response to etoposide. Furthermore, SUV4-20H depletion and the subsequent changes in H4K20 methylation impaired the repair of TOP2-induced DNA breaks by disrupting BRCA1-mediated homologous recombination processes, ultimately leading to extensive cancer cell death and significant inhibition of prostate tumor growth in vivo. Overall, these findings demonstrate that targeting the epigenetic activity of SUV4-20H is a powerful strategy to enhance the efficacy of TOP2 poisons and may represent a therapeutic alternative in prostate cancer, where SUV4-20H2 expression emerges as a potential marker of aggressive disease and high metastatic risk","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"21 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202998","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":"Wilm’s Tumor 1-Expressing Stromal Cells Promote Pancreatic Cancer Progression","authors":"Allison C. Bischoff, Kristee Brown, Emily L. Lasse Opsahl, Hannah R. Watkoske, Carlos E. Espinoza, Jude Ogechukwu. Okoye, Alberto C. Olivei, Leah M. Green, Ridesh Rai, Stephanie The, Wei Yan, Aaron D. denDekker, Eileen S. Carpenter, Jiaqi Shi, Filip Bednar, Timothy L. Frankel, Yaqing Zhang, Marina Pasca di Magliano","doi":"10.1158/0008-5472.can-25-1014","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-1014","url":null,"abstract":"Cancer-associated fibroblasts (CAFs) are a prevalent cell population in the microenvironment of pancreatic cancer. The pancreas harbors diverse resident cell populations that can differentiate into CAFs, and the cell-of-origin might contribute to CAF heterogeneity. Expression of the transcription factor Wilm’s Tumor 1 (WT1) marks mesothelial cells, as well as a transcriptionally distinct population of fibroblasts in the normal pancreas. WT1 expression also identifies a population of CAFs in both human and mouse pancreatic cancer. Here, we investigated the contribution of WT1+ mesenchymal cells to CAF populations and evaluated the functional role of WT1+ stromal cells in pancreatic cancer. Lineage tracing revealed that WT1+ cells expand in pancreatic cancer, where they give rise to a population of inflammatory CAFs. Depletion of WT1+ stromal cells reduced orthotopic tumor growth, with increased immunosuppressive macrophage activation and reduced infiltration of CD8+ and FOXP3+ T cells. Notably, the reduction in tumor weight observed with WT1+ cell depletion was independent of CD8+ and CD4+ T cells. WT1+ CAFs expressed high levels of tumor-promoting ligands that likely interact directly with the tumor epithelium to drive tumor progression. Accordingly, WT1-expressing cell-depleted tumors had reduced epithelial MAPK activation. Together, these data show that WT1+ stromal cells represent a tumor-promoting CAF population. While this population might constitute a potential therapeutic target, caution will be needed to avoid exacerbating immune suppression.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"109 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203143","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":"Alternatively Spliced Citrate Synthase Supports Colorectal Cancer","authors":"Désirée Schatton, Christian Frezza","doi":"10.1158/0008-5472.can-25-3356","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-3356","url":null,"abstract":"Metabolic changes are a major hallmark of cancer with the mitochondrial tricarboxylic acid (TCA) cycle playing a central role in this process. Remodeling of the TCA cycle occurs in cancer cells to sustain the increased anabolic and energetic demands required to grow, proliferate, and metastasize. Alternative splicing (AS) is increasingly recognized as a key regulator of cancer metabolism, yet its specific impact on TCA cycle enzymes remains unclear. In this issue of Cancer Research, Cheung and colleagues describe a novel splicing isoform of citrate synthase (CS), termed CS-ΔEx4, which is highly expressed in colorectal cancer. This CS-ΔEx4 isoform forms heterocomplexes with full-length CS, enhancing CS activity and promoting the metabolic reprogramming characteristic of malignancy. Overexpression of CS-ΔEx4 increases mitochondrial respiration and drives glycolytic carbon flux toward TCA intermediates, resulting in elevated levels of the metabolite 2-hydroxyglutarate. Mechanistically, this increase in 2-hydroxyglutarate, facilitated by increased activity of phosphoglycerate dehydrogenase, leads to epigenetic alterations that support oncogenic gene expression and tumor progression. Suppression of CS-ΔEx4 or pharmacologic inhibition of its activity reverts these metabolic and epigenetic changes, reducing cancer cell survival and metastatic potential. These findings establish a direct link between AS of a core metabolic enzyme and the emergence of cancer hallmarks, suggesting that targeting AS-derived variants like CS-ΔEx4 may represent a promising therapeutic strategy for colorectal cancer and potentially other malignancies in which such isoforms are expressed. See related article by Cheung et al., p. XX","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"109 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202997","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":"Editor's Note: A Novel L-Asparaginase with low L-Glutaminase Coactivity Is Highly Efficacious against Both T- and B-cell Acute Lymphoblastic Leukemias In Vivo.","authors":"Hien Anh Nguyen, Ying Su, Jenny Y Zhang, Aleksandar Antanasijevic, Michael Caffrey, Amanda M Schalk, Li Liu, Damiano Rondelli, Annie Oh, Dolores L Mahmud, Maarten C Bosland, Andre Kajdacsy-Balla, Sofie Peirs, Tim Lammens, Veerle Mondelaers, Barbara De Moerloose, Steven Goossens, Michael J Schlicht, Kasim K Kabirov, Alexander V Lyubimov, Bradley J Merrill, Yogen Sauntharajah, Pieter Van Vlierberghe, Arnon Lavie","doi":"10.1158/0008-5472.CAN-25-3493","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-25-3493","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"85 19","pages":"3812"},"PeriodicalIF":16.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198500","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":"Ceramide Links Alzheimer's Disease to Decreased Cancer Risk: A Lipid Behind the Enigma of Inverse Comorbidity.","authors":"Erhard Bieberich","doi":"10.1158/0008-5472.can-25-2288","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-2288","url":null,"abstract":"For decades, epidemiologic studies have consistently reported an inverse comorbidity between Alzheimer's disease (AD) and cancer: Individuals with AD are less likely to develop cancer and vice versa. The biological basis of this paradox has remained largely unresolved. A study by Kassir and colleagues in this issue of Cancer Research provides a compelling mechanistic insight into this paradox by demonstrating that amyloid precursor protein and its cleavage product Aβ40, known for their pathologic accumulation in the AD brain, also accumulate in peripheral T cells where they suppress mitochondrial ceramide production and lethal autophagy. This preservation of mitochondrial function enhances the antitumor immunity of T cells. Previous work has established that ceramide can promote neurodegeneration in the brain. The suppression of ceramide generation by amyloid precursor protein and Aβ40 in the periphery, thereby preserving mitochondrial integrity and supporting anticancer immunity, further establishes ceramide as a context-dependent regulator of cell fate and a key factor in the inverse AD-cancer relationship. See related article by Kassir et al., p. 3791.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"102 1","pages":"3579-3581"},"PeriodicalIF":11.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194701","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}