RT Journal Article
SR Electronic
T1 NetrinG1/NGL-1 Axis promotes pancreatic tumorigenesis through cancer associated fibroblast derived nutritional supply 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 Linara Gabitova
A1 Tatiana Pazina
A1 Tiffany Luong
A1 Neelima Shah
A1 Dustin Rollins
A1 Sapna Gupta
A1 Roshan Thapa
A1 Diana Restifo
A1 Allison Lau
A1 Yan Zhou
A1 Kathy Q. Cai
A1 Harvey Hensley
A1 Emmanuelle Nicolas
A1 Warren Kruger
A1 Karthik Devarajan
A1 Siddharth Balachandran
A1 Wafik S. El-Deiry
A1 Matthew Vander Heiden
A1 Kerry S. Campbell
A1 Igor Astsaturov
A1 Edna Cukierman
YR 2018
UL http://biorxiv.org/content/early/2018/05/25/330209.1.abstract
AB Pancreatic 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.Significance PDAC has a 5-year survival rate of ∼8% and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets and discern their functional roles. Using patient tissue and data, three-dimensional co-culturing in vitro assays, and orthotopic murine models, we identified NetG1 and NGL-1 as major promoters of PDAC tumorigenesis. NetG1+ CAFs supported PDAC survival, through NetG1/NGL-1 mediated nutritional supply, dependent on glutamate metabolism. NetG1+ CAFs were intrinsically immunosuppressive and inhibited NK cell mediated killing of PDAC cells. NGL-1 controlled tumor cell fitness in vitro and in vivo, likely through metabolic communication with CAFs. Overall, we identified two putative targets in different cellular compartments in PDAC and disrupting solely one arm of the NetG1/NGL-1 axis significantly stunted tumorigenesis.