The tissue microenvironment, composed of stromal cells and extracellular matrix (ECM), is known to contribute to tumor progression, by providing both the structure and signals that promote tumor cell proliferation, survival and invasion. Fibronectin and collagen are major components of the tumor microenvironment, however, how tumor cells gain the ability to respond to these substrate-bound cues and how ECM sensing contributes to promoting metastasis remain poorly understood. Here, using a combination of in vitro and in vivo imaging, we show that gradients of FN can promote directional cell motility of breast cancer cells, a process dependent upon the actin regulatory Mena. Expression of the pro-metastatic isoform MenaINV allows cells to haptotax towards very high concentrations of FN, found near blood vessels and tumor periphery. Haptotaxis requires the direct interaction between α5β1 integrin and Mena/ MenaINV and is driven by outside-in signaling at focal complexes, crosstalk between α5β1 and EGFR, and inside-out tumor cell dependent ECM remodeling. These findings are clinically relevant as patients with high levels of MenaINV protein and FN have increased recurrence and decreased survival in two breast cancer cohorts. Our results identify a novel tumor cell-intrinsic mechanism that promotes ECM remodeling and directed migration, ultimately affecting metastasis.

Citation Format: Madeleine J. Oudin, Oliver Jonas, Tatiana Kosciuk, Liliane Broye, Jeff Wyckoff, Joelle Klazen, John Lamar, Sreeja Asokan, Charlie Whittaker, Robert Langer, Michael Cima, Kari Wisinski, Richard Hynes, Douglas Lauffenburger, Patricia Keely, James Bear, Frank Gertler. Haptotaxis and direct remodeling of the extracellular matrix by tumor cells is important for metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr PR15.