Adipocytes promote pancreatic cancer cell proliferation via glutamine transfer

Abstract

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 regulating in vitro PanIN 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.

Metabolic Interactions in the Tumor Microenvironment

“…Based on the observation that pancreatic cancers depend on glutamine metabolism for survival [67, 68], conditioned media from preadipocytes were also found to contain glutamine, which supported pancreatic cancer cell proliferation in glutamine-free growth media [69] (Fig. 4).…”

“…Similarly, cultured astrocytes can provide glutamine to brain cancer cells [73]. Glutamine sharing metabolic pathways in pancreatic [69], ovarian [59] and brain cancer [73] suggest that targeting metabolic crosstalk pathways specifically involving glutamine will provide new and additional therapeutic targets to treat cancer.…”

Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies

“…Ovarian tumors that thrive on glutamine develop a feedback loop with CAFs whereby tumor cells metabolize glutamine, produce the metabolic byproducts glutamate and lactate, and CAFs then metabolize these back to glutamine (Yang et al, 2016), which is degraded by the tumor cells via a metabolic pathway not utilized by stromal cells found in normal ovary tissue. Pancreatic cancer cells can similarly use adipocyte-derived glutamine to promote cell proliferation (Meyer et al, 2016). In vitro , activated T cells can use increased amounts of glutamine as a metabolic substrate, and exhibit reduced proliferative capacity and cytokine secretion when glutamine concentrations are low (Carr et al, 2010).…”

The potential role of leptin in tumor invasion and metastasis

“…In an in vitro study, murine 3T3L1 adipocytes were co-cultured with pancreatic intraepithelial neoplasia and ductal adenocarcinoma cells derived from PKCY mice. Adipocytes promoted proliferation of both cell types [21]. …”