title: Breast cancer-derived extracellular vesicles stimulate myofibroblast differentiation and pro-angiogenic behavior of adipose stem cells.
abstract: Adipose-derived stem cells (ASCs) are abundantly present in the mammary microenvironment and can promote breast cancer malignancy by differentiating into myofibroblasts. However, it remains largely unclear which role tumor-derived extracellular vesicles (TEVs) play in this process. Here, we used microfabricated, type I collagen-based 3-D tissue culture platforms to investigate the effect of breast cancer cell-derived TEVs on ASCs myofibroblast differentiation and consequential changes in extracellular matrix remodeling and vascular sprouting. TEVs collected from MDA MB-231 human metastatic breast cancer cells (MDAs) promoted ASC myofibroblast differentiation in both 2-D and 3-D cultures as indicated by increased alpha smooth muscle actin (α-SMA) and fibronectin (Fn) levels. Correspondingly, TEV-treated ASCs were more contractile, secreted more vascular endothelial growth factor (VEGF), and promoted angiogenic sprouting of human umbilical vein endothelial cells (HUVECs). These changes were dependent on transforming growth factor beta (TGF-β)-related signaling and tumor cell glutaminase activity as their inhibition decreased TEV-related myofibroblastic differentiation of ASCs and related functional consequences. In summary, our data suggest that TEVs are important signaling factors that contribute to ASC desmoplastic reprogramming in the tumor microenvironment, and suggest that tumor cell glutamine metabolism may be used as a therapeutic target to interfere with this process.
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States.
authors.forename: Young Hye
authors.initials: YH
authors.lastname: Song
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Warncke
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States.
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Choi
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States.
authors.forename: Siyoung
authors.initials: S
authors.lastname: Choi
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States.
authors.forename: Aaron E
authors.initials: AE
authors.lastname: Chiou
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States.
authors.forename: Lu
authors.initials: L
authors.lastname: Ling
authors.affiliation: Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, United States.
authors.forename: Han-Yuan
authors.initials: HY
authors.lastname: Liu
authors.affiliation: Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Daniel
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, NY, United States.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Antonyak
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, NY, United States; Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cerione
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States; Kavli Institute at Cornell for Nanoscale Science, Cornell University, Ithaca, NY, United States. Electronic address: cf99@cornell.edu.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fischbach
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D053119:Benzophenanthridines / Q000494:pharmacology; D015415:Biomarkers; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000737:chemistry*; D000067128:Extracellular Vesicles / Q000737:chemistry*; D005260:Female; D005353:Fibronectins; D005786:Gene Expression Regulation; D005972:Glutaminase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D048056:Mitogen-Activated Protein Kinase 9 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D000911:Antibodies, Monoclonal; D053119:Benzophenanthridines; D015415:Biomarkers; D016207:Cytokines; C067625:FN1 protein, human; D005353:Fibronectins; D016212:Transforming Growth Factor beta; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000598981:compound 968; D048056:Mitogen-Activated Protein Kinase 9; D005972:Glutaminase
keywords: Adipose-derived stem cells; Angiogenesis; Extracellular matrix; Fibronectin; Myofibroblast; Tumor microvesicles