Targeting of MCL-1 in breast cancer associated fibroblasts reverses their myofibroblastic phenotype and pro-invasive properties

Abstract

Cancer associated fibroblasts (CAF) are a major cellular component of epithelial tumors. In breast cancers in particular these stromal cells have numerous tumorigenic effects in part due to their acquisition of a myofibroblastic phenotype. Breast CAFs (bCAFS) typically express MCL-1. We show here that targeting this regulator of mitochondrial integrity using a specific BH-3 mimetic promotes fragmentation of these organelles without inducing cell death. MCL-1 antagonism in primary bCAFs directly derived from human samples mitigates myofibroblastic features and decreases expression of genes involved in actomyosin organization and contractility, associated with a cytoplasmic retention of the transcriptional regulator, Yes-Associated Protein (YAP). Such treatment decreases bCAFs ability to promote cancer cells invasion in 3D co-culture assays. These effects are counteracted by an inhibitor of the mitochondrial fission protein DRP-1, which interacts with MCL-1 upon BH3 mimetic treatment. Our findings underscore the usefulness of targeting MCL-1 in breast cancer ecosystems, not only to favor death of cancer cells but also to counteract the tumorigenic activation of fibroblasts with which they co-evolve.

MCL-1 promiscuity and the structural resilience of its binding partners

“…1). MCL-1 is overexpressed in various tumor variants, which makes it of high interest in therapeutic application 18,[21][22][23][24][25] . At its canonical binding site, MCL-1 promiscuously binds the α-helical binding domain of the BH3-only proteins PUMA, BIM, and NOXA 26,27 , most likely by induced fit [28][29][30][31][32] .…”