A pro-tumorigenic mDia2-MIRO1 axis controls mitochondrial positioning and function in cancer-associated fibroblasts
A recent "Cancer Research" paper by the Werner group (IMHS) discovered that mitochondrial positioning and associated metabolic activities are crucial for cancer-associated fibroblasts to exert their pro-tumorigenic effects. The study also identifies a novel signaling axis as a target for therapeutic intervention.
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Cancer-associated fibroblasts (CAFs) are key regulators of tumorigenesis, but their mechanisms of action remain incompletely understood. The Werner group discovered that mitochondrial positioning and function is essential for CAFs to mediate their pro-tumorigenic effect. Mechanistically, this involves the formin mDia2, which interacts with and stabilizes the mitochondrial trafficking protein MIRO1. Knock-down of mDia2 or MIRO1 in CAFs reduced the presence of mitochondria at CAF-tumor cell-contact sites and caused metabolic reprogramming, ATP depletion, and impaired secretion of pro-tumorigenic proteins. Inhibition of mDia2 or MIRO1 or their common upstream regulator activin A suppressed tumor formation in pre-clinical mouse models for squamous carcinogenesis. The work unveils a key role of mitochondria in the pro-tumorigenic CAF phenotype and identify a signaling axis in CAFs with therapeutic potential.
Link to the publication in "external page Cancer Research".