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. 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.See related commentary by Sherman, p. 230.This article is highlighted in the In This Issue feature, p. 211.
Highlights
Pancreatic cancer is projected to become the 2nd leading cause of cancer related deaths by 2030 [1], due to its abysmal 5 year survival rate [2]
To gain insight into the mechanism by which naive fibroblasts are activated into cancer associated fibroblasts (CAFs), we performed a transcriptomic analysis comparing two sets of patient matched tumor adjacent fibroblasts (TAs) and CAFs (Fig 1A, Sup Table 1) that were cultured in our cell-derived extracellular matrix (ECM) based culturing system that assures maintenance of in vivo-like fibroblastic phenotypes [37, 38]
To characterize the underlying molecular pathways and biological processes, we performed Gene Set Enrichment Analysis (GSEA) and found significant enrichment (Benjamini-Hochberg False Discovery Rate < 0.25) of several pathways previously found to be associated with the transition from normal fibroblasts to CAFs, including upregulation of integrin signaling, focal adhesions, actin cytoskeleton, and ECM (Fig 1B-C, Sup Table 1)
Summary
Pancreatic cancer is projected to become the 2nd leading cause of cancer related deaths by 2030 [1], due to its abysmal 5 year survival rate [2]. PDAC has a unique microenvironment that consists of a fibrous expansion known as desmoplasia, characterized by the deposition of an abundant extracellular matrix (ECM) by cancer associated fibroblasts (CAFs) [5]. Studies have demonstrated that CAFs limit the efficacy of chemotherapies [6,7,8], promote PDAC progression [9, 10], and correlate with poor prognosis [11]. While there is a clear role for CAFs in facilitating PDAC progression, there is evidence that CAFs can be tumor restrictive, as complete ablation of fibroblasts from the tumor microenvironment accelerated PDAC progression [12, 13] and provided no added patient benefit [14]. The role of CAFs in PDAC development and progression is incompletely understood
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