RT Journal Article
SR Electronic
T1 The NetrinG1/NGL-1 Axis promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 330209
DO 10.1101/330209
A1 Ralph Francescone
A1 Débora Barbosa Vendramini-Costa
A1 Janusz Franco-Barraza
A1 Jessica Wagner
A1 Alexander Muir
A1 Allison N. Lau
A1 Linara Gabitova
A1 Tatiana Pazina
A1 Sapna Gupta
A1 Tiffany Luong
A1 Neelima Shah
A1 Dustin Rollins
A1 Ruchi Malik
A1 Roshan Thapa
A1 Diana Restifo
A1 Yan Zhou
A1 Kathy Q. Cai
A1 Harvey H. Hensley
A1 Yinfei Tan
A1 Warren D. Kruger
A1 Karthik Devarajan
A1 Siddharth Balachandran
A1 Wafik S. El-Deiry
A1 Matthew G. Vander Heiden
A1 Suraj Peri
A1 Kerry S. Campbell
A1 Igor Astsaturov
A1 Edna Cukierman
YR 2019
UL http://biorxiv.org/content/early/2019/03/08/330209.abstract
AB Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multi-plex data from patient tissue, three-dimensional co-culturing in vitro assays, and orthotopic murine models, we identified Netrin G1 (NetG1) and Netrin G1 ligand (NGL-1) as promoters of PDAC tumorigenesis. NetG1+ cancer-associated fibroblasts (CAFs) supported PDAC survival, through a NetG1/NGL-1 mediated effect on glutamate/glutamine metabolism. NetG1+ CAFs were intrinsically immunosuppressive and inhibited NK cell mediated killing of tumor cells. These functions were partially mediated by vesicular glutamate transporter 1 and glutamine synthetase. This study uncovered a link between CAF driven metabolism and its immunosuppressive capacity, suggesting NetG1 and NGL-1 as potential targets in PDAC.Significance PDAC is a devastating disease lacking effective therapies. A major hallmark of PDAC is desmoplasia, characterized by the expansion of CAFs and their extracellular matrix, creating a unique microenvironment that limits blood-supplied nutrition and is highly immunosuppressive. Nevertheless, the role of CAFs in PDAC is incompletely understood and new targets in PDAC are needed. Here, we uncovered two potential targets, NetG1 in CAFs and its binding partner NGL-1 in tumor cells. NetG1 in CAFs was important for the metabolic support of PDAC cells and for the intrinsic immunosuppressive capacity of CAFs, while NGL-1 in PDAC cells drove tumorigenesis. Our results helped clarify the role that CAFs play in PDAC, by defining CAF phenotypes through NetG1 expression. Finally, we established a link between CAF driven metabolism and their intrinsic immunosuppressive capacity. Thus, NetG1/NGL-1 axis drove cell reciprocal and cell autonomous functions in PDAC, representing new attractive targets for this aggressive disease.