This is not the latest version of this item. The latest version can be found here.
Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression
Name
nihms-1642553.pdf
Description
Accepted version
Size
3.77 MB
Format
Adobe PDF
Checksum (MD5)
97e09a537c375a2a93e222e48a4f6c4f
Author(s)
Francescone, Ralph
Barbosa Vendramini-Costa, Débora
Franco-Barraza, Janusz
Wagner, Jessica
Muir, Alexander
Lau, Allison N
Gabitova, Linara
Pazina, Tatiana
Gupta, Sapna
Luong, Tiffany
Date Issued
2021
Journal
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Version
Author's final manuscript
Abstract
© 2020 American Association for Cancer Research. 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 multiplex data from patient tissue, three-dimensional coculturing in vitro assays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. We found that NetG1+ cancer-associated fibroblasts (CAF) support PDAC survival, through a NetG1-mediated effect on glutamate/glutamine metabolism. Also, NetG1+ CAFs are intrinsically immunosup-pressive and inhibit natural killer cell–mediated killing of tumor cells. These protumor functions are controlled by a signaling circuit downstream of NetG1, which is comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally, blocking NetG1 with a neutral-izing antibody stunts in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC. SIGNIFICANCE: This study demonstrates the feasibility of targeting a fibroblastic protein, NetG1, which can limit PDAC tumorigenesis in vivo by reverting the protumorigenic properties of CAFs. Moreover, inhibition of metabolic proteins in CAFs altered their immunosuppressive capacity, linking metabolism with immunomodulatory function.
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
10.1158/2159-8290.CD-20-0775
