Endothelial extracellular vesicles promote tumour growth by tumour-associated macrophage reprogramming.

Tumour-derived extracellular vesicles (EVs) participate in tumour progression by deregulating various physiological processes including angiogenesis and inflammation. Here we report that EVs released by endothelial cells in a mammary tumour environment participate in the recruitment of macrophages within the tumour, leading to an immunomodulatory phenotype permissive for tumour growth. Using RNA-Seq approaches, we identified several microRNAs (miRNAs) found in endothelial EVs sharing common targets involved in the regulation of the immune system. To further study the impact of these miRNAs in a mouse tumour model, we focused on three miRNAs that are conserved between humans and mouse, that is, miR-142-5p, miR-183-5p and miR-222-3p. These miRNAs are released from endothelial cells in a tumour microenvironment and are transferred via EVs to macrophages. In mouse mammary tumour models, treatment with EVs enriched in these miRNAs leads to a polarization of macrophages toward an M2-like phenotype, which in turn promotes tumour growth.

Inhibition of the mitochondrial protein Opa1 curtails breast cancer growth.

BACKGROUND: Mitochondrial fusion and fission proteins have been nominated as druggable targets in cancer. Whether their inhibition is efficacious in triple negative breast cancer (TNBC) that almost invariably develops chemoresistance is unknown. METHODS: We used a combination of bioinformatics analyses of cancer genomic databases, genetic and pharmacological Optic Atrophy 1 (OPA1) inhibition, mitochondrial function and morphology measurements, micro-RNA (miRNA) profiling and formal epistatic analyses to address the role of OPA1 in TNBC proliferation, migration, and invasion in vitro and in vivo. RESULTS: We identified a signature of OPA1 upregulation in breast cancer that correlates with worse prognosis. Accordingly, OPA1 inhibition could reduce breast cancer cells proliferation, migration, and invasion in vitro and in vivo. Mechanistically, while OPA1 silencing did not reduce mitochondrial respiration, it increased levels of miRNAs of the 148/152 family known to inhibit tumor growth and invasiveness. Indeed, these miRNAs were epistatic to OPA1 in the regulation of TNBC cells growth and invasiveness. CONCLUSIONS: Our data show that targeted inhibition of the mitochondrial fusion protein OPA1 curtails TNBC growth and nominate OPA1 as a druggable target in TNBC.