Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer

Hugo Croizer, Rana Mhaidly, Yann Kieffer, Geraldine Gentric, Lounes Djerroudi, Renaud Leclere, Floriane Pelon, Catherine Robley, Mylene Bohec, Arnaud Meng, Didier Meseure, Emanuela Romano, Sylvain Baulande, Agathe Peltier, Anne Vincent-Salomon and Fatima Mechta-Grigoriou ()
Additional contact information
Hugo Croizer: PSL Research University
Rana Mhaidly: PSL Research University
Yann Kieffer: PSL Research University
Geraldine Gentric: PSL Research University
Lounes Djerroudi: PSL Research University
Renaud Leclere: Institut Curie Hospital Group
Floriane Pelon: PSL Research University
Catherine Robley: PSL Research University
Mylene Bohec: PSL Research University, ICGex Next-Generation Sequencing Platform
Arnaud Meng: PSL Research University
Didier Meseure: Institut Curie Hospital Group
Emanuela Romano: Center for Cancer Immunotherapy, Institut Curie
Sylvain Baulande: PSL Research University, ICGex Next-Generation Sequencing Platform
Agathe Peltier: PSL Research University
Anne Vincent-Salomon: Institut Curie Hospital Group
Fatima Mechta-Grigoriou: PSL Research University

Nature Communications, 2024, vol. 15, issue 1, 1-28

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47068-z

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