Cancer-secreted miRNAs regulate amino-acid-induced mTORC1 signaling and fibroblast protein synthesis.

Abstract

Metabolic reprogramming of non-cancer cells residing in a tumor microenvironment, as a result of the adaptations to cancer-derived metabolic and non-metabolic factors, is an emerging aspect of cancer-host interaction. We show that in normal and cancer-associated fibroblasts, breast cancer-secreted extracellular vesicles suppress mTOR signaling upon amino acid stimulation to globally reduce mRNA translation. This is through delivery of cancer-derived miR-105 and miR-204, which target RAGC, a component of Rag GTPases that regulate mTORC1 signaling. Following amino acid starvation and subsequent re-feeding, 13 C-arginine labeling of de novo synthesized proteins shows selective translation of proteins that cluster to specific cellular functional pathways. The repertoire of these newly synthesized proteins is altered in fibroblasts treated with cancer-derived extracellular vesicles, in addition to the overall suppressed protein synthesis. In human breast tumors, RAGC protein levels are inversely correlated with miR-105 in the stroma. Our results suggest that through educating fibroblasts to reduce and re-prioritize mRNA translation, cancer cells rewire the metabolic fluxes of amino acid pool and dynamically regulate stroma-produced proteins during periodic nutrient fluctuations.

• Authors: Miranda Y Fong, Wei Yan, Majid Ghassemian, Xiwei Wu, Xin Zhou, Minghui Cao, Li Jiang, Jessica Wang, Xuxiang Liu, Jin Zhang, Shizhen Emily Wang
• Journal: EMBO reports (EMBO Rep) Vol. 22 Issue 2 Pg. e51239 (02 03 2021) ISSN: 1469-3178 [Electronic] England
• PMID: 33345445 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2020 The Authors.

Chemical References

• Amino Acids
• MIRN105 microRNA, human
• MIRN204 microRNA, human
• MicroRNAs
• Mechanistic Target of Rapamycin Complex 1
• Monomeric GTP-Binding Proteins

Topics

• Amino Acids
• Fibroblasts (metabolism)
• Humans
• Mechanistic Target of Rapamycin Complex 1 (genetics, metabolism)
• MicroRNAs (genetics)
• Monomeric GTP-Binding Proteins (metabolism)
• Neoplasms