Tumor cell-driven extracellular matrix remodeling enables haptotaxis during metastatic progression
Author(s)Oudin, Madeleine Julie; Jonas, Oliver H.; Kosciuk, Tatsiana; Broye, Liliane C.; Candido Guido, Bruna; Wyckoff, Jeffrey; Riquelme, Daisy; Lamar, John Michael; Asokan, Sreeja B.; Whittaker, Charles A.; Ma, Duanduan; Langer, Robert; Cima, Michael J.; Wisinski, Kari B.; Hynes, Richard O.; Lauffenburger, Douglas A.; Keely, Patricia J.; Bear, James E.; Gertler, Frank; ... Show more Show less
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Fibronectin (FN) is a major component of the tumor microenvironment, but its role in promoting metastasis is incompletely understood. Here we show that FN gradients elicit directional movement of breast cancer cells, in vitro and in vivo. Haptotaxis on FN gradients requires direct interaction between α5β1 integrin and Mena, an actin regulator, and involves increases in focal complex signaling and tumor-cell-mediated extracellular matrix (ECM) remodeling. Compared to Mena, higher levels of the pro-metastatic MenaINV isoform associate with α5, which enables 3D haptotaxis of tumor cells towards the high FN concentrations typically present in perivascular space and in the periphery of breast tumor tissue. MenaINV and FN levels were correlated in two breast cancer cohorts, and high levels of MenaINV were significantly associated with increased tumor recurrence as well as decreased patient survival. Our results identify a novel tumor-cell-intrinsic mechanism that promotes metastasis through ECM remodeling and ECM guided directional migration.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Biology
American Association for Cancer Research
Oudin, M. J., O. Jonas, T. Kosciuk, L. C. Broye, B. C. Guido, J. Wyckoff, D. Riquelme, et al. “Tumor Cell-Driven Extracellular Matrix Remodeling Enables Haptotaxis During Metastatic Progression.” Cancer Discovery (January 25, 2016).
Author's final manuscript