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 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 coculture 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. Mechanistically, pharmacological inhibition of MCL-1 with a specific BH3 mimetic promotes mitochondrial fragmentation in bCAFs. Inhibition of the mitochondrial fission activity of DRP-1, which interacts with MCL-1 upon BH3 mimetic treatment, allows the maintenance of the myofibroblastic phenotype of bCAFs.

Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials

“…Bonneaud and colleagues unraveled that targeting MCL-1 via BH3 mimetic, an antagonist to various BCL-2 congeners, including MCL-1, can mitigate the invasion of cancer cells and inhibit their tumor-promoting function. A possible mechanism is that BH3 mimetic promotes mitochondrial cleavage in bCAF [ 286 ]. Exosome-based research is in full swing, and exosome-based nucleic acid delivery has become an emerging cancer treatment option [ 287 ].…”

Low BCL-xL expression in triple-negative breast cancer cells favors chemotherapy efficacy, and this effect is limited by cancer-associated fibroblasts

“…A promising strategy for targeting the protumoral effects of CAFs is to reverse their 'activated' phenotype. We have shown that targeting MCL-1 in CAFs attenuates their myofibroblastic phenotype, including a reduction in their pro-invasive capacity 36 . In our study, CAFs protect BCL-xL deficient cancer cells against chemotherapy independently of their own sensitivity to treatments, which is heterogeneous.…”

Butein inhibits oral squamous cell carcinoma growth via promoting MCL-1 ubiquitination

“…breast cancer, colon cancer, multiple myeloma). Existing evidences shows that MCL-1 is closely related to tumorigenesis, immortalization, recurrence, and therapeutic resistance [44][45][46]. Martina et al found that the Mcl-1 gene is necessary for senescent tumor cell proliferation and metastatic dissemination using single-cell RNA-sequencing analysis [47].…”