2. Academic Validation
  3. Cancer-cell-secreted extracellular vesicles suppress insulin secretion through miR-122 to impair systemic glucose homeostasis and contribute to tumour growth

Cancer-cell-secreted extracellular vesicles suppress insulin secretion through miR-122 to impair systemic glucose homeostasis and contribute to tumour growth

  • Nat Cell Biol. 2022 Jun;24(6):954-967. doi: 10.1038/s41556-022-00919-7.
Minghui Cao 1,  Roi Isaac 2,  Wei Yan 1,  Xianhui Ruan 1,  Li Jiang 1,  Yuhao Wan 1,  Jessica Wang 1,  Emily Wang 1,  Christine Caron 1,  Steven Neben 3,  Denis Drygin 3,  Donald P Pizzo 1,  Xiwei Wu 4,  Xuxiang Liu 1,  Andrew R Chin 1,  Miranda Y Fong 1,  Ziting Gao 5,  Kaizhu Guo 5,  Oluwole Fadare 1,  Richard B Schwab 2,  Yuan Yuan 6,  Susan E Yost 6,  Joanne Mortimer 6,  Wenwan Zhong 5,  Wei Ying 2,  Jack D Bui 1,  Dorothy D Sears 2 7 8 9,  Jerrold M Olefsky 2,  Shizhen Emily Wang 10 11
Affiliations

Affiliations

  • 1 Department of Pathology, University of California, San Diego, La Jolla, CA, USA.
  • 2 Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
  • 3 Regulus Therapeutics Inc., San Diego, CA, USA.
  • 4 Department of Molecular and Cellular Biology, City of Hope, Duarte, CA, USA.
  • 5 Department of Chemistry, University of California, Riverside, Riverside, CA, USA.
  • 6 Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA, USA.
  • 7 College of Health Solutions, Arizona State University, Phoenix, AZ, USA.
  • 8 Department of Family Medicine, University of California, San Diego, La Jolla, CA, USA.
  • 9 Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
  • 10 Department of Pathology, University of California, San Diego, La Jolla, CA, USA. [email protected].
  • 11 Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. [email protected].
PMID: 35637408 DOI: 10.1038/s41556-022-00919-7
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.

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