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Journal article
NetrinG1 + cancer-associated fibroblasts generate unique extracellular vesicles that support the survival of pancreatic cancer cells under nutritional stress
Cancer research communications, v 2(9), pp 1017-1036
01 Sep 2022
PMID: 36310768
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
It 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). These pathogenic stroma CAF/ECM units cause the collapse of local blood vessels rendering the tumor microenvironment nutrient-poor. PDAC cells are able to survive this state of nutrient stress via support from CAF-secreted material, which includes small extracellular vesicles (sEVs). The tumor-supportive CAFs possess a distinct phenotypic profile, compared to normal-like fibroblasts, expressing NetrinG1 (NetG1) at the plasma membrane, and active Integrin α β localized to the multivesicular bodies; traits indicative of poor patient survival. We herein report that NetG1 CAFs secrete sEVs that stimulate Akt-mediated survival in nutrient-deprived PDAC cells, protecting them from undergoing apoptosis. Further, we show that NetG1 expression in CAFs is required for the pro-survival properties of sEVs. Additionally, we report that the above-mentioned CAF markers are secreted in distinct subpopulations of EVs; with NetG1 being enriched in exomeres, and Integrin α β being enriched in exosomes. Finally, we found that NetG1 and Integrin α β were detected in sEVs collected from plasma of PDAC patients, while their levels were significantly lower in plasma-derived sEVs of sex/age-matched healthy donors. The discovery of these tumor-supporting CAF-EVs elucidates novel avenues in tumor-stroma interactions and pathogenic stroma detection.
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- Title
- NetrinG1 + cancer-associated fibroblasts generate unique extracellular vesicles that support the survival of pancreatic cancer cells under nutritional stress
- Creators
- Kristopher S Raghavan - Marvin and Concetta Greenberg Pancreatic Cancer Institute, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, USARalph Francescone - Fox Chase Cancer CenterJanusz Franco-Barraza - Fox Chase Cancer CenterJaye C Gardiner - Fox Chase Cancer CenterDébora Barbosa Vendramini-Costa - Fox Chase Cancer CenterTiffany Luong - Fox Chase Cancer CenterNarges Pourmandi - University of MichiganAnthony Andren - University of MichiganAlison Kurimchak - Cancer Signaling and Epigenetics Program, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, USACharline Ogier - Fox Chase Cancer CenterPaul M Campbell - Drexel UniversityJames S Duncan - Cancer Signaling and Epigenetics Program, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, USACostas A Lyssiotis - University of MichiganLucia R Languino - Thomas Jefferson UniversityEdna Cukierman (Corresponding Author) - Fox Chase Cancer Center
- Publication Details
- Cancer research communications, v 2(9), pp 1017-1036
- Number of pages
- 20
- Grant note
- R21 CA231252, R01 CA269660, R01 CA232256, R21 CA252535, P30 CA006927, R03 CA273479, S10 OD023666 / NCI NIH HHS, 20-0081 / Worldwide Cancer Research (Fox Chase) R01 CA248160 / NCI NIH HHS (UM) We dedicate this work to Patricia Keely (pioneer in the field of ECM biology) and Neelima Shah (the most beautiful soul) who continue to inspire our studies. We thank Jane Clifford, Paul Campbell, and Jeffery Peterson for assertive comments during the time experiments were being conducted. We are grateful to Martin Humphries for the SNAKA51 antibody. We thank Rachel DeRita for her insight and expertise in analyzing extracellular vesicles. This work was supported in part by the Pancreatic Cancer Cure Foundation, the Concetta Greenberg Pancreatic Cancer Institute, Pennsylvania's DOH Health Research Formula Funds, the 5th AHEPA Cancer Research Foundation, Inc., a grant by the Worldwide Cancer Research, NIH/NCI grants R21CA231252, R21CA252535, R01CA232256, R01CA269660, S10ODO23666, and the Core Comprehensive Cancer Center Grant CA06927 in support to Fox Chase Cancer Center's facilities including: Bio Sample Repository, Light Microscopy, Biostatistics and Bioinformatics, Immune Monitoring/Histopathology, Cell Culture, and the Talbot Library. The authors also acknowledge grants from the NIH R03CA273479 (P.M. Campbell), the NCI R01CA248160 (C.A. Lyssiotis), ACS-132561-PF-18-218-01-CSM and from the Emerald Foundation/Black-In-Cancer (J.C. Gardiner), as well as two Career Development Awards from the 2021 Pancreatic Cancer Action Network; (i) in memory of Skip Viragh 21-20-FRAN (R. Francescone) and (ii) in support of a French Postdoctoral Fellow (C. Ogier).
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine; Graduate School of Biomedical Sciences and Professional Studies
- Web of Science ID
- WOS:001037092300001
- Scopus ID
- 2-s2.0-85143236559
- Other Identifier
- 991021861212804721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Oncology