Abstract IA025: Local and systemic effects of cancer-cell-secreted extracellular miRNA

Across the many levels of intercellular crosstalk between cancer and niche, extracellular vesicles (EVs) and their cargo molecules such as miRNA play important roles. We previously show that cancer-secreted, EV-encapsulated miRNA metabolically reprogram various non-cancer niche cells to support primary and metastatic tumor growth. Breast-cancer-secreted miR-122 suppresses glucose uptake in brain and lung cells to bias the nutrient competition toward cancer cells during early metastasis. Higher levels of miR-122 and miR-105 in the circulation of early-stage breast cancer patients are associated with metastatic progression. In the study of EV-mediated effects on the metabolic reprogramming of non-cancer cells residing in a tumor microenvironment, we reveal a mechanism involving breast-cancer-secreted, EV-encapsulated miR-105, which is induced by the oncoprotein MYC in cancer cells and in turn activates MYC signaling in cancer-associated fibroblasts (CAFs) to induce a metabolic program. This results in CAFs’ capacity to display different metabolic features in response to changes in the metabolic environment. When nutrients are sufficient, miR-105-reprogrammed CAFs enhance glucose and glutamine metabolism to fuel adjacent cancer cells. When nutrients are deprived whereas metabolic byproducts are accumulated, these CAFs detoxify metabolic wastes, including lactic acid and ammonium, by converting them into energy-rich metabolites. Thus, the miR-105-mediated metabolic reprogramming of stromal cells contributes to sustained tumor growth by conditioning the shared metabolic environment. As others have shown that the majority of carbon mass in cells is derived from amino acids (AAs) consumed at relatively low rates, we further investigate how cancer-cell-secreted EVs influence the biosynthetic fate of AAs in fibroblasts. In normal and cancer-associated fibroblasts, breast-cancer-secreted EVs suppress mTOR signaling upon AA 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 AA starvation and subsequent re-feeding, 13C-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 EVs, in addition to the overall suppressed protein synthesis. In human breast tumors, RAGC protein levels are inversely correlated with miR-105 in the stroma. These results suggest that through educating fibroblasts to reduce and re-prioritize mRNA translation, cancer cells rewire the metabolic fluxes of AA pool and dynamically regulate stroma-produced proteins during periodic nutrient fluctuations. Our recent studies thus reveal the complex metabolic reprogramming effects of cancer-cell-secreted extracellular miRNA. These local and systemic effects exhibit a dependency on the various niche cell context. Citation Format: Shizhen Emily Wang. Local and systemic effects of cancer-cell-secreted extracellular miRNA [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA025.