Netrin G1 promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression

Abstract

SummaryPancreatic ductal adenocarcinoma (PDAC) is a devastating disease lacking effective therapies. A major hallmark of PDAC is desmoplasia, characterized by the expansion of cancer-associated fibroblasts (CAFs) and their extracellular matrix, creating a unique microenvironment that limits blood-supplied nutrition and is highly immunosuppressive. Here, we uncovered the upregulation of NetrinG1 (NetG1) in CAFs and its binding partner NetrinG1 ligand (NGL-1) in PDAC cells and patient tissue samples. Using a three-dimensional culturing system, we observed that the NetG1/NGL-1 axis controls key pro-tumorigenic features of CAFs and PDAC cells, in cell autonomous and reciprocal manners. Results were confirmed in vivo using patient tissues and in a murine PDAC model in which NGL-1 ablation in PDAC cells significantly halted tumor growth. Thus, this study identifies two potential targets for PDAC, both tumoral and microenvironmental.

Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma

“…Another approach that has been used to determine which cell type(s) within the tumor contribute to a metabolic activity is isolating distinct cell populations and studying them in culture (Dalin et al, 2019;Francescone et al, 2018;Linares et al, 2017;Sousa et al, 2016;Valencia et al, 2014;Yang et al, 2016). Pancreatic stellate cells (PSCs) are a type of resident fibroblast in the pancreas which can become activated during tumorigenesis and impact the tumor microenvironment (Bynigeri et al, 2017;Dunér et al, 2011).…”

“…For instance, cancer cells are a minority cell type in pancreatic ductal adenocarcinoma (PDAC) tumors ( Feig et al, 2012 ), and an understanding of cell metabolism in these tumors requires de-convolution of cancer-specific and stroma-specific phenotypes. Furthermore, there is evidence that the metabolism of cancer cells and different stromal cells isolated from these tumors can be different from each other when studied in culture ( Francescone et al, 2018 ; Halbrook et al, 2019 ; Sousa et al, 2016 ), and it is unknown whether the metabolic programs used by different cell populations in culture are also used within PDAC tumors in vivo where environmental conditions are different.…”

CD36 and CD97 in Pancreatic Cancer versus Other Malignancies

“…Recent studies have illustrated that glutaminase expression was increased in CAFs compared to pancreatic tumoral cells, being the reason for which CAFs were more sensitive to glutamine removal than tumoral cells [100,160]. It was also observed that CAFs secrete greater levels of glutamate and glutamine in culture, sustaining the growth of pancreatic tumoral cells, compared to normal PSCs [161]. Nevertheless, future studies are needed to elucidate the role of glutamine metabolism in fibroblasts [100].…”

Interactions with stromal cells promote a more oxidized cancer cell redox state in pancreatic tumors

“…Metabolite exchange has also been reported between cell types in pancreatic cancer cells based on physical contact. For example, cell-cell interactions between the glutamatergic pre-synaptic protein Netrin G1 in CAFs and its receptor NGL-1 in PDAC cells can play a role glutamate/glutamine sharing between cell types 69 . Regardless of the mechanism, when taken together the data presented argue that direct interactions between PSCs and cancer cells can promote a more oxidized state in the cancer cells, and suggest that redox sharing is another way by which cell-cell interactions between cancer cells and stromal cells can support pancreatic cancer metabolism and tumor growth.…”