MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment that commonly support cancer development and progression. Here we show that different cancer cells transfer mitochondria to fibroblasts in co-cultures and xenograft tumors, thereby inducing pro-tumorigenic CAF features. Transplantation of functional mitochondria from cancer cells induces metabolic alterations in fibroblasts, expression of CAF markers, and release of a pro-tumorigenic secretome and matrisome. These features promote tumor formation in pre-clinical mouse models. Mechanistically, the mitochondrial transfer requires the mitochondrial trafficking protein MIRO2. Its depletion in cancer cells suppresses mitochondrial transfer and inhibits CAF differentiation and tumor growth. The clinical relevance of these findings is reflected by the overexpression of MIRO2 in tumor cells at the leading edge of epithelial skin cancers. These results identify mitochondrial transfer from cancer cells to fibroblasts as a driver of tumorigenesis and provide a rationale for targeting MIRO2 and mitochondrial transfer in different malignancies. To assess the functional relevance of the mitochondrial transfer, we sorted viable primary human dermal fibroblasts with high and low MitoTracker Green fluorescence intensity from co-cultures with A431 cancer cells and analyzed the two populations by RNA sequencing (RNA-seq). Control fibroblasts subjected to the sorting procedure, but not maintained in co-cultures, were included for comparison. Three replicates are included in each condition.