The tumor microenvironment (TME) is increasingly recognized as a critical modulator of the initiation, progression, metastasis, and therapeutic resistance of various cancers. Cancer-associated fibroblasts (CAFs), the predominant stromal cell population within the TME, play pivotal roles in these processes through their remarkable phenotypic and functional heterogeneity. Emerging evidence underscores the diversity in the origins, phenotypes, and functions of CAFs, highlighting their ability to adaptively influence tumor biology in a context-dependent manner. CAFs facilitate cancer malignancy via multiple interconnected mechanisms, including the secretion of soluble bioactive factors, the release of exosomes, the metabolic reprogramming of tumor cells, the remodeling of the extracellular matrix (ECM), and the modulation of the immune microenvironment. CAFs have emerged as attractive and viable therapeutic targets. Recent efforts have focused on developing therapies that disrupt the protumorigenic activities of CAFs or reprogram them toward tumor-suppressive phenotypes. Several of these strategies have shown promise and are advancing into clinical trials. In this review, we comprehensively discuss recent advancements in our understanding of the heterogeneity of CAFs, elucidate their multifaceted interactions within the TME, and explore novel therapeutic strategies targeting CAFs across various cancer types. Our review aims to foster the translation of preclinical insights into clinically effective interventions targeting CAFs.
{"title":"Cancer-associated fibroblasts in the tumor microenvironment: heterogeneity, crosstalk mechanisms, and therapeutic implications.","authors":"Ziyue Huang,Jie Chen,Tianyu Zhu,Jinxin Li,Ho Yin Ng,Yixiong Zhou,Xiang Gu,Shiqiong Xu,Renbing Jia","doi":"10.1186/s12943-025-02533-1","DOIUrl":"https://doi.org/10.1186/s12943-025-02533-1","url":null,"abstract":"The tumor microenvironment (TME) is increasingly recognized as a critical modulator of the initiation, progression, metastasis, and therapeutic resistance of various cancers. Cancer-associated fibroblasts (CAFs), the predominant stromal cell population within the TME, play pivotal roles in these processes through their remarkable phenotypic and functional heterogeneity. Emerging evidence underscores the diversity in the origins, phenotypes, and functions of CAFs, highlighting their ability to adaptively influence tumor biology in a context-dependent manner. CAFs facilitate cancer malignancy via multiple interconnected mechanisms, including the secretion of soluble bioactive factors, the release of exosomes, the metabolic reprogramming of tumor cells, the remodeling of the extracellular matrix (ECM), and the modulation of the immune microenvironment. CAFs have emerged as attractive and viable therapeutic targets. Recent efforts have focused on developing therapies that disrupt the protumorigenic activities of CAFs or reprogram them toward tumor-suppressive phenotypes. Several of these strategies have shown promise and are advancing into clinical trials. In this review, we comprehensively discuss recent advancements in our understanding of the heterogeneity of CAFs, elucidate their multifaceted interactions within the TME, and explore novel therapeutic strategies targeting CAFs across various cancer types. Our review aims to foster the translation of preclinical insights into clinically effective interventions targeting CAFs.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"24 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777317","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 : 2025-12-18DOI: 10.1186/s12943-025-02527-z
Erik Rasbach,Laure Migayron,Anne Brandenburg,Praveen Singh,Christina Martins,Ali Kassem,Anastasia I Karkempetzaki,Nadine Suessner,Zsofi Kulcsar,Jessica Riopedre,Mariana Silva,Ethan Zhen,Shuyun Xu,Kyla Mucciarone,Julia Holzgruber,Jason B Williams,Emrullah Birgin,Mitchell P Levesque,Julia M Martínez-Gómez,Reinhard Dummer,Jennifer Landsberg,Christine G Lian,George F Murphy,Emma L Berdan,Shannan Ho Sui,Thomas S Kupper,Nuh N Rahbari,Nayoung Lee,Steven R Barthel,Tobias Schatton
BACKGROUNDITGB2 is a critical integrin mediator of immune cell activation and trafficking. Its expression has been claimed as exclusive to hematopoietic cells. Consequently, the significance of cancer cell-intrinsic ITGB2 in solid tumor progression and therapy has not been rigorously evaluated.METHODSWe leveraged single-cell and bulk RNA sequencing, real-time quantitative PCR, multiplex immunofluorescence, flow cytometry, immunoblotting, and intercellular adhesion molecule (ICAM)-1-dependent adhesion and proliferation assays to uncover melanoma cell-intrinsic ITGB2 functional expression, association with clinical tumor progression, activation, protumorigenic signaling, adhesive and proliferative functions utilizing patient melanoma biospecimens, established human and murine melanoma lines. In vivo tumorigenicity studies in immunocompromised NOD/SCID interleukin-2 receptor γ chain null (NSG), immunocompetent wildtype, and Icam1 knockout (KO) C57BL/6 mice were performed to dissect melanoma-ITGB2 downstream pathway activity and functions in tumor growth and metastasis. The cancer cell-intrinsic ITGB2 axis was targeted using CRISPR/Cas9-based Itgb2 KO, blocking ITGB2 antibodies, ITGB2-activating CD44 crosslinking, and pharmacologic inhibition of ITGB2-dependent Wnt signaling using LGK974, zamaporvint, and FDA-approved pyrvinium pamoate repurposed for cancer therapy.RESULTSThis work demonstrates nonhematopoietic expression and protumorigenic functions of ITGB2 intrinsic to melanoma cells. Tumor cell-ITGB2 mediated adhesion to ICAM-1, promoted cancer progression in preclinical melanoma models, was enriched in clinical metastatic versus primary melanomas or benign nevi, and predicted sentinel lymph node metastasis in patients with primary disease. Consistently, inhibition of melanoma cell-intrinsic ITGB2 using blocking antibodies or Itgb2 gene KO potently suppressed ICAM-1-mediated melanoma cell adhesion, tumor growth, and metastatic dissemination. Melanoma cell-ITGB2:ICAM-1 interaction activated downstream Wnt signaling, the pharmacologic inhibition of which suppressed melanoma-ITGB2-mediated tumorigenesis.CONCLUSIONSThis work overturns the longstanding paradigm that ITGB2 is restricted to leukocytes by discovering a tumor cell-intrinsic ITGB2:ICAM-1:Wnt protumorigenic axis as a bona fide cancer therapeutic target in melanoma.
{"title":"Targeting the tumor cell-intrinsic ITGB2 axis inhibits melanoma progression.","authors":"Erik Rasbach,Laure Migayron,Anne Brandenburg,Praveen Singh,Christina Martins,Ali Kassem,Anastasia I Karkempetzaki,Nadine Suessner,Zsofi Kulcsar,Jessica Riopedre,Mariana Silva,Ethan Zhen,Shuyun Xu,Kyla Mucciarone,Julia Holzgruber,Jason B Williams,Emrullah Birgin,Mitchell P Levesque,Julia M Martínez-Gómez,Reinhard Dummer,Jennifer Landsberg,Christine G Lian,George F Murphy,Emma L Berdan,Shannan Ho Sui,Thomas S Kupper,Nuh N Rahbari,Nayoung Lee,Steven R Barthel,Tobias Schatton","doi":"10.1186/s12943-025-02527-z","DOIUrl":"https://doi.org/10.1186/s12943-025-02527-z","url":null,"abstract":"BACKGROUNDITGB2 is a critical integrin mediator of immune cell activation and trafficking. Its expression has been claimed as exclusive to hematopoietic cells. Consequently, the significance of cancer cell-intrinsic ITGB2 in solid tumor progression and therapy has not been rigorously evaluated.METHODSWe leveraged single-cell and bulk RNA sequencing, real-time quantitative PCR, multiplex immunofluorescence, flow cytometry, immunoblotting, and intercellular adhesion molecule (ICAM)-1-dependent adhesion and proliferation assays to uncover melanoma cell-intrinsic ITGB2 functional expression, association with clinical tumor progression, activation, protumorigenic signaling, adhesive and proliferative functions utilizing patient melanoma biospecimens, established human and murine melanoma lines. In vivo tumorigenicity studies in immunocompromised NOD/SCID interleukin-2 receptor γ chain null (NSG), immunocompetent wildtype, and Icam1 knockout (KO) C57BL/6 mice were performed to dissect melanoma-ITGB2 downstream pathway activity and functions in tumor growth and metastasis. The cancer cell-intrinsic ITGB2 axis was targeted using CRISPR/Cas9-based Itgb2 KO, blocking ITGB2 antibodies, ITGB2-activating CD44 crosslinking, and pharmacologic inhibition of ITGB2-dependent Wnt signaling using LGK974, zamaporvint, and FDA-approved pyrvinium pamoate repurposed for cancer therapy.RESULTSThis work demonstrates nonhematopoietic expression and protumorigenic functions of ITGB2 intrinsic to melanoma cells. Tumor cell-ITGB2 mediated adhesion to ICAM-1, promoted cancer progression in preclinical melanoma models, was enriched in clinical metastatic versus primary melanomas or benign nevi, and predicted sentinel lymph node metastasis in patients with primary disease. Consistently, inhibition of melanoma cell-intrinsic ITGB2 using blocking antibodies or Itgb2 gene KO potently suppressed ICAM-1-mediated melanoma cell adhesion, tumor growth, and metastatic dissemination. Melanoma cell-ITGB2:ICAM-1 interaction activated downstream Wnt signaling, the pharmacologic inhibition of which suppressed melanoma-ITGB2-mediated tumorigenesis.CONCLUSIONSThis work overturns the longstanding paradigm that ITGB2 is restricted to leukocytes by discovering a tumor cell-intrinsic ITGB2:ICAM-1:Wnt protumorigenic axis as a bona fide cancer therapeutic target in melanoma.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"31 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777319","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}
BACKGROUNDOsteosarcoma demonstrates limited responsiveness to PD-1 blockade, largely due to its immunosuppressive tumor microenvironment (TME). The specific mechanisms by which cancer-associated fibroblasts (CAFs) contribute to immunosuppression in osteosarcoma are not fully understood.METHODSWe performed single-cell RNA sequencing (scRNA-seq) on osteosarcoma tissues from patients treated with neoadjuvant chemotherapy and anti-PD-1 therapy to investigate the tumor microenvironment. Cellular composition, gene expression programs, and signaling pathways were analyzed. Functional assays, pull-down and PLA-flow binding validation, and in vivo mouse models were used to dissect the mechanisms by which CAF-derived factors influence CD8⁺ T cell function and contribute to immunotherapy response.RESULTSWe identified a subpopulation of CD36⁺ CAFs, characterized by adaptive uptake of oxidized low-density lipoprotein (OxLDL) and activation of the PPARG-FABP4 axis. This metabolic program promoted ANGPTL4 secretion, which bound integrin on CD8⁺ T cells and activated the JAK2-STAT3 pathway, leading to T cell exhaustion and impaired effector function. In vivo, administration of VitE effectively scavenged OxLDL, reprogrammed the TME, enhanced CD8⁺ T cell infiltration, and synergized with PD-1 blockade to improve tumor control.CONCLUSIONSCD36⁺ CAFs drive immunosuppressive metabolic reprogramming via the OxLDL-PPARG-ANGPTL4 axis, promoting CD8⁺ T cell exhaustion and resistance to immunotherapy in osteosarcoma. Targeting this pathway with VitE alleviated CAF-mediated immune suppression and enhanced PD-1 blockade responses in preclinical models, providing a rationale for metabolism-based combinatorial strategies in osteosarcoma.
{"title":"Targeting OxLDL-mediated CD36 + CAF reprogramming potentiates PD-1 immunotherapy in osteosarcoma.","authors":"Anyu Zeng,Hongmin Chen,Tianqi Luo,Weiqing Chen,Yihui Song,Yanyang Xu,Zhihao Chen,Qinglian Tang,Xiaojun Zhu,Chuangzhong Deng,Huaiyuan Xu,Anqi Wang,Hao Wu,Guohui Song,Jinchang Lu,Jin Wang","doi":"10.1186/s12943-025-02516-2","DOIUrl":"https://doi.org/10.1186/s12943-025-02516-2","url":null,"abstract":"BACKGROUNDOsteosarcoma demonstrates limited responsiveness to PD-1 blockade, largely due to its immunosuppressive tumor microenvironment (TME). The specific mechanisms by which cancer-associated fibroblasts (CAFs) contribute to immunosuppression in osteosarcoma are not fully understood.METHODSWe performed single-cell RNA sequencing (scRNA-seq) on osteosarcoma tissues from patients treated with neoadjuvant chemotherapy and anti-PD-1 therapy to investigate the tumor microenvironment. Cellular composition, gene expression programs, and signaling pathways were analyzed. Functional assays, pull-down and PLA-flow binding validation, and in vivo mouse models were used to dissect the mechanisms by which CAF-derived factors influence CD8⁺ T cell function and contribute to immunotherapy response.RESULTSWe identified a subpopulation of CD36⁺ CAFs, characterized by adaptive uptake of oxidized low-density lipoprotein (OxLDL) and activation of the PPARG-FABP4 axis. This metabolic program promoted ANGPTL4 secretion, which bound integrin on CD8⁺ T cells and activated the JAK2-STAT3 pathway, leading to T cell exhaustion and impaired effector function. In vivo, administration of VitE effectively scavenged OxLDL, reprogrammed the TME, enhanced CD8⁺ T cell infiltration, and synergized with PD-1 blockade to improve tumor control.CONCLUSIONSCD36⁺ CAFs drive immunosuppressive metabolic reprogramming via the OxLDL-PPARG-ANGPTL4 axis, promoting CD8⁺ T cell exhaustion and resistance to immunotherapy in osteosarcoma. Targeting this pathway with VitE alleviated CAF-mediated immune suppression and enhanced PD-1 blockade responses in preclinical models, providing a rationale for metabolism-based combinatorial strategies in osteosarcoma.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"40 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777322","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 efficacy of immune checkpoint inhibitors (ICIs) in microsatellite stable colorectal cancer (MSS CRC) remains limited, highlighting an urgent need for predictive biomarkers. Through multi-omics analysis, we identified two novel MSS CRC subtypes, termed DUB-H and DUB-L. The DUB-L subtype exhibited an inflamed tumor immune microenvironment, a superior response to immune therapy, and better recurrence-free survival (RFS) compared to DUB-H. The classifier gene USP7 was selected as a gene of interest due to its specific expression profile, which is highly expressed in MSS CRC but not in microsatellite instability-high (MSI-H) tumors, and strongly correlated with suppressed immune infiltration. Large-scale clinical analyses confirmed associations between high USP7 expression, microsatellite stability, specific consensus molecular subtypes (CMS), and unfavorable prognosis. Single-cell analysis and multiplex immunofluorescence validated an immune-desert phenotype in USP7-high MSS tumors. Mechanistically, USP7 knockdown in MSS CRC cells enhances the secretion of T-cell-recruiting chemokines (CXCL9/10/11), promoting CD8⁺ T cell recruitment and cytotoxicity in vitro. In vivo experiments demonstrated that USP7 blockade enhanced the efficacy of anti-PD-1 treatment in MSS CRC models by remodeling the tumor immune microenvironment, increasing infiltration and function of CD8⁺ T and NK cells. Consistently, low USP7 expression is associated with a better response to anti-PD-1 therapy. Overall, we propose a novel DUB-based classification system for MSS CRC and demonstrate that targeting USP7 may overcome immunotherapy resistance by converting immunologically "cold" tumors into "hot" ones.
{"title":"Immune-related deubiquitylation spectrum of microsatellite stability colorectal cancer reveals USP7 as a potential immunotherapeutic target.","authors":"Xiaomao Yin,Jinran Wu,Mi-Die Xu,Tongguan Tian,Lin Zhu,Jiexuan Wang,Xuan Dai,Xin Yang,Jingjing Qian,Wenqiang Wang,Liangchen Zhu,Zekun Zhao,Kai Xu,Yanping Xu,Xinxing Li,Zhiqian Hu","doi":"10.1186/s12943-025-02502-8","DOIUrl":"https://doi.org/10.1186/s12943-025-02502-8","url":null,"abstract":"The efficacy of immune checkpoint inhibitors (ICIs) in microsatellite stable colorectal cancer (MSS CRC) remains limited, highlighting an urgent need for predictive biomarkers. Through multi-omics analysis, we identified two novel MSS CRC subtypes, termed DUB-H and DUB-L. The DUB-L subtype exhibited an inflamed tumor immune microenvironment, a superior response to immune therapy, and better recurrence-free survival (RFS) compared to DUB-H. The classifier gene USP7 was selected as a gene of interest due to its specific expression profile, which is highly expressed in MSS CRC but not in microsatellite instability-high (MSI-H) tumors, and strongly correlated with suppressed immune infiltration. Large-scale clinical analyses confirmed associations between high USP7 expression, microsatellite stability, specific consensus molecular subtypes (CMS), and unfavorable prognosis. Single-cell analysis and multiplex immunofluorescence validated an immune-desert phenotype in USP7-high MSS tumors. Mechanistically, USP7 knockdown in MSS CRC cells enhances the secretion of T-cell-recruiting chemokines (CXCL9/10/11), promoting CD8⁺ T cell recruitment and cytotoxicity in vitro. In vivo experiments demonstrated that USP7 blockade enhanced the efficacy of anti-PD-1 treatment in MSS CRC models by remodeling the tumor immune microenvironment, increasing infiltration and function of CD8⁺ T and NK cells. Consistently, low USP7 expression is associated with a better response to anti-PD-1 therapy. Overall, we propose a novel DUB-based classification system for MSS CRC and demonstrate that targeting USP7 may overcome immunotherapy resistance by converting immunologically \"cold\" tumors into \"hot\" ones.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"89 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777320","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 : 2025-12-16DOI: 10.1186/s12943-025-02523-3
Shiqi Ren,Xinyi Zhou,Zhen Wang,Kefei Yuan
Metabolic reprogramming of amino acids has been recognized as a significant characteristic in various types of cancers. Numerous studies have indicated that the metabolic reprogramming of amino acids in tumors significantly supports certain malignant behaviors, including tumor proliferation, survival, invasion, and even immune escape. Amino acids can provide biomolecules such as nucleotides and glutathione (GSH) for tumors, and the bioavailability of amino acids influences tumor progression. Meanwhile, as essential metabolites, amino acids are closely associated with immune cell activation and can contribute to tumor immune processes by modulating the function of immune cells. Thus, targeting amino acids metabolism has emerged as a promising therapeutic strategy. Herein, we provide an overview of the effects of amino acids on the central carbon cycle and autophagy. We also provide an in-depth review of potential therapies for cancer treatment associated with amino acids, including metabolic enzymes of amino acids, dietary therapy of amino acids, and so on. Furthermore, we summarize some current nano-systems relevant to amino acids. This review aims to offer a theoretical foundation for understanding amino acids metabolism in cancer and identifying potential therapeutic strategies.
{"title":"Amino acids metabolism: a potential target for cancer treatment.","authors":"Shiqi Ren,Xinyi Zhou,Zhen Wang,Kefei Yuan","doi":"10.1186/s12943-025-02523-3","DOIUrl":"https://doi.org/10.1186/s12943-025-02523-3","url":null,"abstract":"Metabolic reprogramming of amino acids has been recognized as a significant characteristic in various types of cancers. Numerous studies have indicated that the metabolic reprogramming of amino acids in tumors significantly supports certain malignant behaviors, including tumor proliferation, survival, invasion, and even immune escape. Amino acids can provide biomolecules such as nucleotides and glutathione (GSH) for tumors, and the bioavailability of amino acids influences tumor progression. Meanwhile, as essential metabolites, amino acids are closely associated with immune cell activation and can contribute to tumor immune processes by modulating the function of immune cells. Thus, targeting amino acids metabolism has emerged as a promising therapeutic strategy. Herein, we provide an overview of the effects of amino acids on the central carbon cycle and autophagy. We also provide an in-depth review of potential therapies for cancer treatment associated with amino acids, including metabolic enzymes of amino acids, dietary therapy of amino acids, and so on. Furthermore, we summarize some current nano-systems relevant to amino acids. This review aims to offer a theoretical foundation for understanding amino acids metabolism in cancer and identifying potential therapeutic strategies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"56 1","pages":"307"},"PeriodicalIF":37.3,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765479","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 : 2025-12-16DOI: 10.1186/s12943-025-02543-z
Jaehun Lee,Soomin Kim,Youngchul Oh,Stephan R Jahn,Jihoon Kim,Yeongjun Kim,Tim Schmäche,Sang-Min Kim,Isaree Teriyapirom,Thomas Groß,Ohbin Kwon,Jungmin Kim,Somi Kim,Anne-Marlen Ada,Andrea Català-Bordes,Youngwon Cho,Jinho Kim,Amanda Andersson-Rolf,Sebastian R Merker,Joo Yeon Lim,Ji-Yeon Park,Thomas M Klompstra,Ki-Jun Yoon,Dae-Sik Lim,Ho-Seok Lee,Jong Kyoung Kim,Eunyoung Choi,James R Goldenring,Jae-Ho Cheong,Hyunki Kim,Daniel E Stange,Heetak Lee,Bon-Kyoung Koo,Ji-Hyun Lee
BACKGROUNDWNT signaling plays a key role in maintaining the gastric epithelium and promoting tumorigenesis. However, how gastric tumors achieve WNT niche independence remains unclear, as mutations on APC or CTNNB1-common mechanisms of ligand-independent WNT activation in colorectal cancer-are infrequent in gastric cancer. Understanding how WNT self-sufficiency is acquired in the stomach is therefore critical.METHODSWe analyzed mouse gastric organoids harboring oncogenic KRASG12D with or without RNF43/ZNRF3 (RZ) or CDH1/TP53 (CP) mutations, along with corresponding in vivo mouse models. Niche independence was assessed through growth factor withdrawal, Porcupine and pathway-specific inhibitor treatments, and WNT rescue assays. We performed single-nucleus multiome sequencing (RNA + ATAC) to investigate transcriptional and chromatin dynamics. Findings from mouse models were validated using patient-derived gastric cancer organoids, and pan-cancer cell line datasets were analyzed to evaluate clinical and cross-tissue relevance.RESULTSGastric fibroblasts secreted canonical WNT2B to maintain the homeostatic gastric epithelium. Upon KRAS activation, epithelial cells were reprogrammed to secrete WNT ligands independently of additional mutations. Single-nucleus multiome analysis revealed that KRAS-driven MAPK signaling opened SMAD2/3-bound enhancers at the WNT7B locus, leading to the emergence of WNT7B-expressing subpopulations. Inhibition of SMAD2/3 phosphorylation suppressed both organoid growth and WNT7B transcription, whereas exogenous WNT restored organoid proliferation. Patient-derived organoids with HER2 amplification, KRAS amplification, or WNT2 copy-number gain exhibited Porcupine inhibitor-sensitive growth, indicating dependence on WNT secretion from the organoids. Analysis of public transcriptomic datasets further demonstrated that the KRAS-MAPK-WNT7B axis is conserved across other cancer types, including lung cancer.CONCLUSIONSGastric tumors can bypass niche dependence by acquiring KRAS-MAPK-SMAD2/3-driven epithelial WNT secretion. Targeting this axis-through MAPK inhibition, SMAD2/3 blockade, or suppression of WNT secretion-may represent a therapeutic vulnerability in gastric cancer and other KRAS-high malignancies.
{"title":"Epithelial WNT secretion drives niche escape of developing gastric cancer.","authors":"Jaehun Lee,Soomin Kim,Youngchul Oh,Stephan R Jahn,Jihoon Kim,Yeongjun Kim,Tim Schmäche,Sang-Min Kim,Isaree Teriyapirom,Thomas Groß,Ohbin Kwon,Jungmin Kim,Somi Kim,Anne-Marlen Ada,Andrea Català-Bordes,Youngwon Cho,Jinho Kim,Amanda Andersson-Rolf,Sebastian R Merker,Joo Yeon Lim,Ji-Yeon Park,Thomas M Klompstra,Ki-Jun Yoon,Dae-Sik Lim,Ho-Seok Lee,Jong Kyoung Kim,Eunyoung Choi,James R Goldenring,Jae-Ho Cheong,Hyunki Kim,Daniel E Stange,Heetak Lee,Bon-Kyoung Koo,Ji-Hyun Lee","doi":"10.1186/s12943-025-02543-z","DOIUrl":"https://doi.org/10.1186/s12943-025-02543-z","url":null,"abstract":"BACKGROUNDWNT signaling plays a key role in maintaining the gastric epithelium and promoting tumorigenesis. However, how gastric tumors achieve WNT niche independence remains unclear, as mutations on APC or CTNNB1-common mechanisms of ligand-independent WNT activation in colorectal cancer-are infrequent in gastric cancer. Understanding how WNT self-sufficiency is acquired in the stomach is therefore critical.METHODSWe analyzed mouse gastric organoids harboring oncogenic KRASG12D with or without RNF43/ZNRF3 (RZ) or CDH1/TP53 (CP) mutations, along with corresponding in vivo mouse models. Niche independence was assessed through growth factor withdrawal, Porcupine and pathway-specific inhibitor treatments, and WNT rescue assays. We performed single-nucleus multiome sequencing (RNA + ATAC) to investigate transcriptional and chromatin dynamics. Findings from mouse models were validated using patient-derived gastric cancer organoids, and pan-cancer cell line datasets were analyzed to evaluate clinical and cross-tissue relevance.RESULTSGastric fibroblasts secreted canonical WNT2B to maintain the homeostatic gastric epithelium. Upon KRAS activation, epithelial cells were reprogrammed to secrete WNT ligands independently of additional mutations. Single-nucleus multiome analysis revealed that KRAS-driven MAPK signaling opened SMAD2/3-bound enhancers at the WNT7B locus, leading to the emergence of WNT7B-expressing subpopulations. Inhibition of SMAD2/3 phosphorylation suppressed both organoid growth and WNT7B transcription, whereas exogenous WNT restored organoid proliferation. Patient-derived organoids with HER2 amplification, KRAS amplification, or WNT2 copy-number gain exhibited Porcupine inhibitor-sensitive growth, indicating dependence on WNT secretion from the organoids. Analysis of public transcriptomic datasets further demonstrated that the KRAS-MAPK-WNT7B axis is conserved across other cancer types, including lung cancer.CONCLUSIONSGastric tumors can bypass niche dependence by acquiring KRAS-MAPK-SMAD2/3-driven epithelial WNT secretion. Targeting this axis-through MAPK inhibition, SMAD2/3 blockade, or suppression of WNT secretion-may represent a therapeutic vulnerability in gastric cancer and other KRAS-high malignancies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"150 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759964","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 : 2025-12-15DOI: 10.1186/s12943-025-02486-5
D Bakırdöğen, K Görgülü, J Xin, L Richter, S Alcalá, L Ruiz-Cañas, C Dai, K J Frank, N Wu, K N Diakopoulos, H Ozturk, D Demircioğlu, K Peschke, R Ranjan, F Fusco, J Martinez-Useros, M J Fernandez-Aceñero, N F Chhabra, J C López-Gil, J Ai, D A Ruess, E Kaya-Aksoy, F Schmidt, L Kohlmann, A Berninger, H Yangin, F Schicktanz, K Steiger, I E Demir, R M Schmid, M Reichert, M Adli, M Lesina, B Sainz, H Algül
{"title":"c-Rel drives pancreatic cancer metastasis through fibronectin-integrin signaling-induced isolation stress resistance and EMT.","authors":"D Bakırdöğen, K Görgülü, J Xin, L Richter, S Alcalá, L Ruiz-Cañas, C Dai, K J Frank, N Wu, K N Diakopoulos, H Ozturk, D Demircioğlu, K Peschke, R Ranjan, F Fusco, J Martinez-Useros, M J Fernandez-Aceñero, N F Chhabra, J C López-Gil, J Ai, D A Ruess, E Kaya-Aksoy, F Schmidt, L Kohlmann, A Berninger, H Yangin, F Schicktanz, K Steiger, I E Demir, R M Schmid, M Reichert, M Adli, M Lesina, B Sainz, H Algül","doi":"10.1186/s12943-025-02486-5","DOIUrl":"10.1186/s12943-025-02486-5","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":" ","pages":""},"PeriodicalIF":33.9,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145763358","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}
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