Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression
Abstract
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 immunosuppressive 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 neutralizing antibody stunts in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 01, 2021
- Source ID
- 10.1158/2159-8290.cd-20-0775
Entities
People
- Alexander Muir
- Allison N Lau
- Andres J. Klein-szanto
- Diana Restifo
- Dustin Rollins
- Débora Barbosa Vendramini-Costa
- Edna Cukierman
- Harvey H. Hensley
- Huamin Wang
- Igor Astsaturov
- Janusz Franco-Barraza
- Jessica Wagner
- Karthik Devarajan
- Kathy Q. Cai
- Kerry S Campbell
- Linara Gabitova
- Matthew G Vander Heiden
- Ralph Francescone
- Roshan J. Thapa
- Ruchi Malik
- Sapna Gupta
- Siddharth Balachandran
- Suraj Peri
- Tatiana Pazina
- Tiffany Luong
- Wafik S. El-deiry
- Warren D Kruger
- Yan Zhou
- Yinfei Tan
Organizations
- Brown University
- Lankenau Institute for Medical Research
- Massachusetts Institute of Technology
- National Cancer Institute
- University of Chicago
- University of Texas at Austin