3D collagen architecture induces a conserved migratory and transcriptional response linked to vasculogenic mimicry

• Published in: Nature communications Vol. 8; no. 1; pp. 1651 - 12
• Main Authors: Velez, D O, Tsui, B, Goshia, T, Chute, C L, Han, A, Carter, H, Fraley, S I
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 21.11.2017; Nature Publishing Group UK; Nature Portfolio
• Subjects: Architecture; Bulk density; Cancer; Cell adhesion & migration; Cell migration; Cell Movement; Collagen; Collagen - chemistry; Collagen - genetics; Collagen - metabolism; Gene Expression Regulation, Neoplastic; Humans; Hypoxia; Integrin beta1 - genetics; Integrin beta1 - metabolism; Metastases; Mimicry; Neoplasms - genetics; Neoplasms - metabolism; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - physiopathology; Network formation; Short fibers; Stiffness; Transcription; Tumor Microenvironment
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-01556-7

The topographical organization of collagen within the tumor microenvironment has been implicated in modulating cancer cell migration and independently predicts progression to metastasis. Here, we show that collagen matrices with small pores and short fibers, but not Matrigel, trigger a conserved transcriptional response and subsequent motility switch in cancer cells resulting in the formation of multicellular network structures. The response is not mediated by hypoxia, matrix stiffness, or bulk matrix density, but rather by matrix architecture-induced β1-integrin upregulation. The transcriptional module associated with network formation is enriched for migration and vasculogenesis-associated genes that predict survival in patient data across nine distinct tumor types. Evidence of this gene module at the protein level is found in patient tumor slices displaying a vasculogenic mimicry (VM) phenotype. Our findings link a collagen-induced migration program to VM and suggest that this process may be broadly relevant to metastatic progression in solid human cancers.