Abstract
AbstractIt is projected that, in 5 years, pancreatic cancer will become the second deadliest cancer in the United States. A unique aspect of pancreatic ductal adenocarcinoma (PDAC) is its stroma; rich in cancer-associated fibroblasts (CAFs) and a dense CAF-generated extracellular matrix (ECM). This fibrous stroma, known as desmoplasia, causes the collapse of local blood vessels rendering a nutrient-deprived milieu. Hence, PDAC cells are nurtured by local CAF-secreted products, which include, among others, CAF-generated small extracellular vesicles (sEVs). It is well-accepted that upon culturing functionally tumor-promoting CAFs under pathophysiological-relevant conditions (e.g., within self-produced ECM), these cells express NetrinG1 (NetG1) and sustain endosomal pools rich in active α5β1-integrin; traits indicative of poor patient survival. We herein report that NetG1+ CAFs generate sEVs that rescue PDAC cells from nutrient-deprived induced apoptosis. Two unique sEVs, NetG1+ and α5β1-integrin+, were uncovered. The former constitutes cargo of CAF-generated exomeres, and the latter is detected in classic exosomes. Proteomic and metabolomic analyses showed that the sEV-dependent PDAC survival is, at least in part, dictated by the cargo packaged within sEVs in a NetG1-dependent manner. Indeed, despite producing a similar number of vesicles, selected key proteins and metabolites (e.g., glutamine) were incorporated within the unique sEVs. Finally, we found that NetG1 and α5β1-integrin were detected in sEVs collected from plasma of PDAC patients, while their concomitant levels were significantly lower in plasma of sex/age-matched healthy donors. The discovery of these tumor-supporting CAF sEVs opens a new investigative avenue in tumor-stroma interactions and stroma staging detection.
Publisher
Cold Spring Harbor Laboratory
Reference74 articles.
1. Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors
2. SEER*Stat Database Incidence - SEER Research Data, R., Nov 2020 Sub (1975-2018) - Linked To County Attributes - Time Dependent (1990-2018) Income/Rurality, 1969-2019 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, released April 2021, based on the November 2020 submission., 2019.
3. Cancer Statistics, 2021
4. Estimated Projection of US Cancer Incidence and Death to 2040;JAMA Network Open,2021
5. Tumor-stroma interactions in pancreatic ductal adenocarcinoma
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