title: Breast cancer cells alter the dynamics of stromal fibronectin-collagen interactions.
abstract: Breast cancer cells recruit surrounding stromal cells, such as cancer-associated fibroblasts (CAFs), to remodel their extracellular matrix (ECM) and promote invasive tumor growth. Two major ECM components, fibronectin (Fn) and collagen I (Col I), are known to interact with each other to regulate cellular behavior. In this study, we seek to understand how Fn and Col I interplay and promote a dysregulated signaling pathway to facilitate tumor progression. Specifically, we investigated the evolution of tumor-conditioned stromal ECM composition, structure, and relaxation. Furthermore, we assessed how evolving Fn-Col I interactions gradually affected pro-angiogenic signaling. Our data first indicate that CAFs initially assembled a strained, viscous, and unfolded Fn matrix. This early altered Fn matrix was later remodeled into a thick Col I-rich matrix that was characteristic of a dense tumor mass. Next, our results suggest that this ECM remodeling was primarily mediated by matrix metalloproteinases (MMPs). This MMP activity caused profound structural and mechanical changes in the developing ECM, which then modified vascular endothelial growth factor (VEGF) secretion by CAFs and matrix sequestration. Collectively, these findings enhance our understanding of the mechanisms by which Fn and Col I synergistically interplay in promoting a sustained altered signaling cascade to remodel the breast tumor stroma for invasive breast tumor growth.
authors: Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14583, USA; Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14583, USA.
authors: Karin
authors: K
authors: Wang
authors: Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14583, USA.
authors: Fei
authors: F
authors: Wu
authors: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14583, USA.
authors: Bo Ri
authors: BR
authors: Seo
authors: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14583, USA.
authors: Claudia
authors: C
authors: Fischbach
authors: Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14583, USA.
authors: Weisi
authors: W
authors: Chen
authors: Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14583, USA.
authors: Lauren
authors: L
authors: Hsu
authors: Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14583, USA; Department of Physics, University of Ottawa, Ottawa, ON, K1N 6N5, Canada. Electronic address: dg434@cornell.edu.
authors: Delphine
authors: D
authors: Gourdon
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004548:Elasticity; D005109:Extracellular Matrix / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D005353:Fibronectins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D014783:Viscosity
chemical_list: D024042:Collagen Type I; D016207:Cytokines; C067625:FN1 protein, human; D005353:Fibronectins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D020782:Matrix Metalloproteinases
keywords: Breast cancer; Cancer-associated fibroblasts; Collagen I; Extracellular matrix; Fibronectin; Pro-angiogenic signaling