Effect of MCL-1 antagonist in breast cancer associated fibroblasts

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 pharmacological inhibition or knock down of this regulator of mitochondrial integrity in primary bCAFs directly derived from human samples mitigates myofibroblastic features. This decreases expression of genes involved in actomyosin organization and contractility (associated with a cytoplasmic retention of the transcriptional regulator, Yes-Associated Protein - YAP) and decreases bCAFs ability to promote cancer cells invasion in 3D co-culture assays. 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. Comparative gene expression profiling analysis of RNA-seq data for breast cancer associated fibroblasts treated or not by MCL1 antagonsit (S63845, 500 nM, 18h).