RNA-seq analysis with isolated human pancreatic islets treated with human breast cancer cell secreted Evs or control

Epidemiological evidence has identified an association between breast cancer (BC) and systemic dysregulation of glucose metabolism. However, how BC influences glucose homeostasis remains unknown. Here we show that BC-derived extracellular vesicles (EVs) suppress pancreatic endocrine secretion to systemically reset glucose homeostasis. In pancreatic β-cells, miR-122 delivered in BC-derived EVs targets PKM to suppress glycolysis and ATP-dependent insulin exocytosis. Mice receiving high-miR-122 EVs or bearing BC xenograft tumors, but not those with tumors deficient in EV secretion or miR-122, exhibit suppressed insulin secretion, enhanced endogenous glucose production, impaired glucose tolerance, and hyperglycemia. Compared to non-cancer controls, BC patients have higher levels of EV-encapsulated miR-122 and fasting glucose but lower insulin levels in blood; the miR-122 levels are positively associated with glucose and negatively associated with insulin. This EV-mediated glucose reallocation at the whole-body level may contribute to tumor growth and progression, as well as higher incidence of diabetes in BC patients. Human pancreatic islets were isolated from non-diabetic human subjects and purchased from Lonza, California. PBS, Evs secreted from human breast cancer cell line MDA-MB-231 or from non-tumorigenic epithelial cells MCF-10A was added into cultured human pancreatic islets every 24 hours for twice. For each treatment, duplicates were included. Total RNA was extracted 24 hours after the second treatment and used for RNA-seq done by Novogene company.