RT Journal Article
SR Electronic
T1 Netrin G1 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 Andres J. Klein-Szanto
A1 Huamin Wang
A1 Wafik S. El-Deiry
A1 Matthew G. Vander Heiden
A1 Suraj Peri
A1 Kerry S. Campbell
A1 Igor Astsaturov
A1 Edna Cukierman
YR 2020
UL http://biorxiv.org/content/early/2020/05/30/330209.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) as a promoter of PDAC tumorigenesis. NetG1+ cancer-associated fibroblasts (CAFs) supported PDAC survival, through a NetG1 mediated effect on glutamate/glutamine metabolism. NetG1+ CAFs were intrinsically immunosuppressive and inhibited NK cell mediated killing of tumor cells. These pro-tumor functions were controlled by a signaling circuit downstream to NetG1, which was comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally blocking NetG1 with a neutralizing antibody stunted in vivo tumorigenesis, suggesting NetG1 as potential target 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. A better understanding of the role of CAFs in PDAC may lead to the identification of new targets for therapeutic intervention. Here, we uncovered roles for NetG1 in CAFs to promote tumorigenesis. NetG1 was important for two major CAF functions: the metabolic support of PDAC cells and the intrinsic immunosuppressive capacity of CAFs. Our results helped clarify the role that CAFs play in PDAC, by defining CAF phenotypes through NetG1 expression. Moreover, we established a link between CAF driven metabolism and their intrinsic immunosuppressive capacity, and identified a signaling circuit that governs NetG1 functions. Finally, we demonstrated the therapeutic potential of inhibiting NetG1 in vivo by limiting tumorigenesis in mice with a neutralizing antibody, illustrating that targeting stromal NetG1 could be an attractive therapeutic approach.Competing Interest StatementThe authors have declared no competing interest.