Single-cell analysis reveals diverse stromal subsets associated with immune evasion in triple-negative breast cancer
Single-cell analysis reveals diverse stromal subsets associated with immune evasion in triple-negative breast cancer
Abstract The tumour stroma regulates nearly all stages of carcinogenesis. Stromal heterogeneity in human triple-negative breast cancers (TNBCs) remains poorly understood, limiting the development of stromal-targeted therapies. Single cell RNA-sequencing of five TNBCs revealed two cancer-associated fibroblast (CAF) and two perivascular-like (PVL) subpopulations. CAFs clustered into two states, the first with features of myofibroblasts and the second characterised by high expression of growth factors and immunomodulatory molecules. PVL cells clustered into two states consistent with a differentiated and immature phenotype. We showed that these stromal states have distinct morphologies, spatial relationships and functional properties in regulating the extracellular matrix. Using cell-signalling predictions, we provide evidence that stromal-immune crosstalk acts via a diverse array of immunoregulatory molecules. Importantly, the investigation of gene signatures from inflammatory-CAFs and differentiated-PVL cells in independent TNBC patient cohorts revealed strong associations with cytotoxic T-cell dysfunction and exclusion, respectively. Such insights present promising candidates to further investigate for new therapeutic strategies in the treatment of TNBCs.
Powell Joseph、Gluch Laurence、Roden Daniel L.、Wang Chenfei、Torpy James R.、Junankar Simon、Holliday Holly、Timpson Paul、Lim Elgene、Forrest Alistair、Swarbrick Alexander、Segara Davendra、Wu Sunny Z.、Cazet Aur¨|lie S.、Cooper Caroline、Robbins Elizabeth、Cox Thomas R.、Bartonicek Nenad、Hou Rui、Murphy Kendelle J.、Lam Eric、Pereira Brooke、Parker Andrew、Mak Cindy、O?ˉToole Sandra、Warrier Sanjay、Chan Chia-Ling、Al-Eryani Ghamdan、Beith Jane、Hui Mun N.、Harvey Kate、Liu X. Shirley
Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research||UNSW Cellular Genomics Futures Institute, University of New South WalesThe Strathfield Breast CentreThe Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of MedicineDepartment of Data Sciences, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public HealthThe Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of MedicineThe Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of MedicineThe Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of MedicineThe Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of MedicineThe Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of Medicine||St Vincent?ˉs HospitalHarry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia||RIKEN Center for Integrative Medical SciencesThe Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of MedicineSt Vincent?ˉs HospitalThe Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of MedicineThe Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of MedicinePathology Queensland, Princess Alexandra Hospital||Southside Clinical Unit, Faculty of Medicine, University of QueenslandRoyal Prince Alfred HospitalThe Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of MedicineThe Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of MedicineHarry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western AustraliaThe Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of MedicineGarvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical ResearchThe Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of MedicineSt Vincent?ˉs HospitalChris O?ˉBrien LifehouseThe Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of Medicine||Australian Clinical Laboratories, Northern Beaches HospitalDepartment of Breast Surgery, Chris O?ˉBrien Lifehouse||Royal Prince Alfred Institute of Academic Surgery, Sydney UniversityGarvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical ResearchThe Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of MedicineChris O?ˉBrien LifehouseThe Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research||Chris O?ˉBrien LifehouseThe Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical ResearchDepartment of Data Sciences, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health
肿瘤学基础医学细胞生物学
Cancer associated fibroblastssingle cell RNA sequencingstromal heterogeneitytriple negative breast cancertumour microenvironment
Powell Joseph,Gluch Laurence,Roden Daniel L.,Wang Chenfei,Torpy James R.,Junankar Simon,Holliday Holly,Timpson Paul,Lim Elgene,Forrest Alistair,Swarbrick Alexander,Segara Davendra,Wu Sunny Z.,Cazet Aur¨|lie S.,Cooper Caroline,Robbins Elizabeth,Cox Thomas R.,Bartonicek Nenad,Hou Rui,Murphy Kendelle J.,Lam Eric,Pereira Brooke,Parker Andrew,Mak Cindy,O?ˉToole Sandra,Warrier Sanjay,Chan Chia-Ling,Al-Eryani Ghamdan,Beith Jane,Hui Mun N.,Harvey Kate,Liu X. Shirley.Single-cell analysis reveals diverse stromal subsets associated with immune evasion in triple-negative breast cancer[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2020.06.04.135327.点此复制
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