Membrane Peptolytic Signals on a Fibroblast Subset Dictate Cancer Stem Cell Fate by Regulating Lipid Metabolism

Carcinoma-associated fibroblasts (CAFs) consist of heterogeneous subpopulations and play a critical role in the dynamics of the tumor microenvironment. Previously, the extracellular signals of CAFs have been attributed to extracellular matrix, cytokine, cell-surface checkpoints and exosome. Here, we showed that CD10, which is a transmembrane hydrolase expressed on a subset of CAFs, supports tumor stemness and induced chemoresistance. Mechanistically, CD10 degenerates an anti-tumoral peptide, osteogenic growth peptide (OGP). OGP restrains the expression of a rate-limiting desaturase and inhibits lipid desaturation which is required for cancer stem cells (CSCs). Therapeutically, targeting CD10 significantly improves the efficacy of chemotherapy in vivo. Clinically, CD10-OGP signals are associated with the response of neo-adjuvant chemotherapy in patients of breast cancer. Overall, our data suggested that a nexus between the niche and lipid metabolism in CSCs can be a promising therapeutic target for breast cancer. Transcriptome profile of MCF-7mammo treated with or without osteogenic growth peptide (OGP) were generated by deep sequencing using Illumina Novaseq™ 6000.