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- Title
Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer.
- Authors
Croizer, Hugo; Mhaidly, Rana; Kieffer, Yann; Gentric, Geraldine; Djerroudi, Lounes; Leclere, Renaud; Pelon, Floriane; Robley, Catherine; Bohec, Mylene; Meng, Arnaud; Meseure, Didier; Romano, Emanuela; Baulande, Sylvain; Peltier, Agathe; Vincent-Salomon, Anne; Mechta-Grigoriou, Fatima
- Abstract
Although heterogeneity of FAP+ Cancer-Associated Fibroblasts (CAF) has been described in breast cancer, their plasticity and spatial distribution remain poorly understood. Here, we analyze trajectory inference, deconvolute spatial transcriptomics at single-cell level and perform functional assays to generate a high-resolution integrated map of breast cancer (BC), with a focus on inflammatory and myofibroblastic (iCAF/myCAF) FAP+ CAF clusters. We identify 10 spatially-organized FAP+ CAF-related cellular niches, called EcoCellTypes, which are differentially localized within tumors. Consistent with their spatial organization, cancer cells drive the transition of detoxification-associated iCAF (Detox-iCAF) towards immunosuppressive extracellular matrix (ECM)-producing myCAF (ECM-myCAF) via a DPP4- and YAP-dependent mechanism. In turn, ECM-myCAF polarize TREM2+ macrophages, regulatory NK and T cells to induce immunosuppressive EcoCellTypes, while Detox-iCAF are associated with FOLR2+ macrophages in an immuno-protective EcoCellType. FAP+ CAF subpopulations accumulate differently according to the invasive BC status and predict invasive recurrence of ductal carcinoma in situ (DCIS), which could help in identifying low-risk DCIS patients eligible for therapeutic de-escalation. The heterogeneity of cancer associated fibroblasts (CAFs) in breast cancer has been previously described. Here the authors provide further insights into the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer.
- Subjects
BREAST cancer; FIBROBLASTS; REGULATORY T cells; MYOFIBROBLASTS; EXTRACELLULAR matrix; CARCINOMA in situ; BREAST
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-47068-z