Adipocytes promote pancreatic cancer cell proliferation via glutamine transfer.
Adipocytes promote progression of multiple cancers, but their role in pancreatic intraepithelial neoplasia (PanIN) and ductal adenocarcinoma (PDAC) is poorly defined. Nutrient transfer is a mechanism underlying stromal cell-cancer crosstalk. We studied the role of adipocytes in regulatingin vitroPanIN and PDAC cell proliferation with a focus on glutamine metabolism. Murine 3T3L1 adipocytes were used to model adipocytes. Cell lines derived from PKCY mice were used to model PanIN and PDAC. Co-culture was used to study the effect of adipocytes on PanIN and PDAC cell proliferation in response to manipulation of glutamine metabolism. Glutamine secretion was measured with a bioanalyzer. Western blotting was used to study the effect of PanIN and PDAC cells on expression of glutamine-related enzymes in adipocytes. Adipocytes promote proliferation of PanIN and PDAC cells, an effect that was amplified in nutrient-poor conditions. Adipocytes secrete glutamine and rescue PanIN and PDAC cell proliferation in the absence of glutamine, an effect that was glutamine synthetase-dependent and involved PDAC cell-induced down-regulation of glutaminase expression in adipocytes. These findings suggest glutamine transfer as a potential mechanism underlying adipocyte-induced PanIN and PDAC cell proliferation.
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
Kevin A
KA
Meyer
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
Christopher K
CK
Neeley
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
Nicki A
NA
Baker
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
Alexandra R
AR
Washabaugh
Undergraduate Research Opportunity Program, University of Michigan, Ann Arbor, MI, USA.
Carmen G
CG
Flesher
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
Barbara S
BS
Nelson
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Surgery, Ann Arbor Veteran's Administration Hospital, Ann Arbor, MI, USA.
Timothy L
TL
Frankel
Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
Carey N
CN
Lumeng
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
Costas A
CA
Lyssiotis
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Division of Hematology and Oncology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
Michelle L
ML
Wynn
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Andrew D
AD
Rhim
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Surgery, Ann Arbor Veteran's Administration Hospital, Ann Arbor, MI, USA.
Robert W
RW
O'Rourke
3T3L1; adipocyte; glutamine; pancreatic cancer; pancreatic intraepithelial neoplasia