Targeting stromal remodeling and cancer stem cell plasticity to overcome chemoresistance in triple negative breast cancer
Targeting stromal remodeling and cancer stem cell plasticity to overcome chemoresistance in triple negative breast cancer
ABSTRACT The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hh ligand produced by neoplastic cells reprogrammed cancer-associated fibroblast (CAF) gene expression, driving tumor growth and metastasis. Hh-activated CAFs upregulated expression of FGF5 and production of fibrillar collagen, leading to FGFR and FAK activation in adjacent neoplastic cells, which then acquired a stem-like, drug-resistant phenotype. Treatment with smoothened inhibitors (SMOi) reversed these phenotypes. Stromal treatment of TNBC patient-derived xenograft (PDX) models with SMOi downregulated the expression of cancer stem cell markers and sensitized tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. Markers of pathway activity correlated with response. These studies identify Hh signaling to CAFs as a novel mediator of cancer stem cell plasticity and an exciting new therapeutic target in TNBC. SIGNIFICANCECompared to other breast cancer subtypes, TNBCs are associated with significantly worse patient outcomes. Standard of care systemic treatment for patients with non-BRCA1/2 positive TNBC is cytotoxic chemotherapy. However, the failure of 70% of treated TNBCs to attain complete pathological response reflects the relative chemoresistance of these tumors. New therapeutic strategies are needed to improve patient survival and quality of life. Here, we provide new insights into the dynamic interactions between heterotypic cells within a tumor. Specifically, we establish the mechanisms by which CAFs define cancer cell phenotype and demonstrate that the bidirectional CAF-cancer cell crosstalk can be successfully targeted in mice and humans using anti-stromal therapy.
Cazet Aur¨|lie S.、Nair Radhika、Elsworth Benjamin L.、Lim Elgene、Samuel Michael、Mart¨an Miguel、Swarbrick Alexander、Hui Mun N.、Chan Chia-Ling、Harvey Kate、Johan M. Zahied、Cooper Caroline、Herrmann David、Yang Jessica、Ruiz-Borrego Manuel、Cox Thomas R.、McFarland Andrea、Caballero Rosal¨aa、Timpson Paul、Watkins D. Neil、Rojo Federico、O?ˉToole Sandra、Skhinas Joanna N.、Roden Daniel、Trigo Jos¨| M.、Deng Nian-Tao、Bezares Susana、Wu Sunny Z.、Collot Rapha?l
Garvan Institute of Medical Research||The Kinghorn Cancer Centre, Darlinghurst||St Vincent?ˉs Clinical SchoolRajiv Gandhi Centre for BiotechnologyMRC Integrative Epidemiology Unit, University of BristolGarvan Institute of Medical Research||The Kinghorn Cancer Centre, Darlinghurst||St Vincent?ˉs Clinical School||St Vincent?ˉs HospitalCentre for Cancer Biology||Faculty of Health Sciences, School of Medicine, University of AdelaideDepartment of Medical Oncology, Instituto de Investigaci¨?n Sanitaria Gregorio Mara?¨?n, Universidad ComplutenseGarvan Institute of Medical Research||The Kinghorn Cancer Centre, Darlinghurst||St Vincent?ˉs Clinical SchoolGarvan Institute of Medical Research||The Kinghorn Cancer Centre, Darlinghurst||The Chris O?ˉ Brien Lifehouse||Royal Prince Alfred HospitalGarvan Institute of Medical Research||The Kinghorn Cancer Centre, DarlinghurstGarvan Institute of Medical Research||The Kinghorn Cancer Centre, DarlinghurstCentre for Cancer Biology||Faculty of Health Sciences, School of Medicine, University of AdelaidePathology Queensland and School of Medicine, University of QueenslandGarvan Institute of Medical Research||The Kinghorn Cancer Centre, Darlinghurst||St Vincent?ˉs Clinical SchoolGarvan Institute of Medical Research||The Kinghorn Cancer Centre, DarlinghurstDepartment of Medical OncologyGarvan Institute of Medical Research||The Kinghorn Cancer Centre, Darlinghurst||St Vincent?ˉs Clinical SchoolGarvan Institute of Medical Research||The Kinghorn Cancer Centre, DarlinghurstGEICAM (Spanish Breast Cancer Group)Garvan Institute of Medical Research||The Kinghorn Cancer Centre, Darlinghurst||St Vincent?ˉs Clinical SchoolGarvan Institute of Medical Research||The Kinghorn Cancer Centre, Darlinghurst||St Vincent?ˉs Clinical School||St Vincent?ˉs HospitalDepartment of PathologyGarvan Institute of Medical Research||The Kinghorn Cancer Centre, Darlinghurst||Royal Prince Alfred HospitalGarvan Institute of Medical Research||The Kinghorn Cancer Centre, DarlinghurstGarvan Institute of Medical Research||The Kinghorn Cancer Centre, Darlinghurst||St Vincent?ˉs Clinical SchoolDepartment of Medical OncologyGarvan Institute of Medical Research||The Kinghorn Cancer Centre, DarlinghurstGEICAM (Spanish Breast Cancer Group)Garvan Institute of Medical Research||The Kinghorn Cancer Centre, Darlinghurst||St Vincent?ˉs Clinical SchoolGarvan Institute of Medical Research||The Kinghorn Cancer Centre, Darlinghurst
肿瘤学基础医学分子生物学
Cancer stem cell plasticityextracellular matrixcancer-associated fibroblaststranslational breast cancer researchdevelopmental signaling pathway
Cazet Aur¨|lie S.,Nair Radhika,Elsworth Benjamin L.,Lim Elgene,Samuel Michael,Mart¨an Miguel,Swarbrick Alexander,Hui Mun N.,Chan Chia-Ling,Harvey Kate,Johan M. Zahied,Cooper Caroline,Herrmann David,Yang Jessica,Ruiz-Borrego Manuel,Cox Thomas R.,McFarland Andrea,Caballero Rosal¨aa,Timpson Paul,Watkins D. Neil,Rojo Federico,O?ˉToole Sandra,Skhinas Joanna N.,Roden Daniel,Trigo Jos¨| M.,Deng Nian-Tao,Bezares Susana,Wu Sunny Z.,Collot Rapha?l.Targeting stromal remodeling and cancer stem cell plasticity to overcome chemoresistance in triple negative breast cancer[EB/OL].(2025-03-28)[2025-05-10].https://www.biorxiv.org/content/10.1101/215954.点此复制
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