Tumor cell-driven extracellular matrix remodeling enables haptotaxis during metastatic progression

• Main Authors: Oudin, Madeleine Julie (Contributor), Jonas, Oliver H. (Contributor), Kosciuk, Tatsiana (Contributor), Broye, Liliane C. (Contributor), Candido Guido, Bruna (Contributor), Wyckoff, Jeffrey (Contributor), Asokan, Sreeja B. (Author), Whittaker, Charles A. (Contributor), Ma, Duanduan (Contributor), Cima, Michael J. (Contributor), Wisinski, Kari B. (Author), Keely, Patricia J. (Author), Bear, James E. (Author), Gertler, Frank (Contributor), Riquelme, Daisy Noelia (Author), Lamar, John (Author), Langer, Robert S (Author), Hynes, Richard O (Author), Lauffenburger, Douglas A (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Massachusetts Institute of Technology. Department of Biology (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor), Riquelme, Daisy (Contributor), Lamar, John Michael (Contributor), Langer, Robert (Contributor), Hynes, Richard O. (Contributor), Lauffenburger, Douglas A. (Contributor)
• Format: Article
• Language: English
• Published: American Association for Cancer Research, 2016-03-22T20:22:15Z.
• Subjects: Article
• Online Access: Get fulltext

 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.