@article{4ca241e79e3041959ea4c14474ccb6d7,
title = "Cancer-cell-secreted extracellular vesicles suppress insulin secretion through miR-122 to impair systemic glucose homeostasis and contribute to tumour growth",
abstract = "Epidemiological studies demonstrate an association between breast cancer (BC) and systemic dysregulation of glucose metabolism. However, how BC influences glucose homeostasis remains unknown. We show that BC-derived extracellular vesicles (EVs) suppress pancreatic insulin secretion to impair glucose homeostasis. EV-encapsulated miR-122 targets PKM in β-cells to suppress glycolysis and ATP-dependent insulin exocytosis. Mice receiving high-miR-122 EVs or bearing BC tumours exhibit suppressed insulin secretion, enhanced endogenous glucose production, impaired glucose tolerance and fasting hyperglycaemia. These effects contribute to tumour growth and are abolished by inhibiting EV secretion or miR-122, restoring PKM in β-cells or supplementing insulin. Compared with non-cancer controls, patients with BC have higher levels of circulating EV-encapsulated miR-122 and fasting glucose concentrations but lower fasting insulin; miR-122 levels are positively associated with glucose and negatively associated with insulin. Therefore, EV-mediated impairment of whole-body glycaemic control may contribute to tumour progression and incidence of type 2 diabetes in some patients with BC.",
author = "Minghui Cao and Roi Isaac and Wei Yan and Xianhui Ruan and Li Jiang and Yuhao Wan and Jessica Wang and Emily Wang and Christine Caron and Steven Neben and Denis Drygin and Pizzo, {Donald P.} and Xiwei Wu and Xuxiang Liu and Chin, {Andrew R.} and Fong, {Miranda Y.} and Ziting Gao and Kaizhu Guo and Oluwole Fadare and Schwab, {Richard B.} and Yuan Yuan and Yost, {Susan E.} and Joanne Mortimer and Wenwan Zhong and Wei Ying and Bui, {Jack D.} and Sears, {Dorothy D.} and Olefsky, {Jerrold M.} and Wang, {Shizhen Emily}",
note = "Funding Information: This work was supported by the National Institutes of Health (NIH)/National Cancer Institute (NCI) grants R01CA218140 (S.E.W.), R01CA206911 (S.E.W.) and R01CA179977 (D.D.S.). J.D.B. is supported by a grant from the Hartwell Foundation. Research reported in this publication included work performed in the core facilities supported by the NIH/NCI under grant number P30CA23100 (UCSD Moores Cancer Center) and in the City of Hope Integrative Genomics Core supported by NIH/NCI under grant number P30CA33572. The authors would like to thank the UCSD/CMM EM facility for EM sample preparation. The EM facility is supported by NIH equipment grant 1S10OD023527. We thank X. Xiao for kindly providing plasmid pEMBOL-D(+)-Ins-GFP. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2022",
month = jun,
doi = "10.1038/s41556-022-00919-7",
language = "English (US)",
volume = "24",
pages = "954--967",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "6",
}