Abstract 2301: Myeloid cells promote fibroblast invasion and lead mammary adenocarcinoma cell invasion.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Myeloid cells localize to invasive edges of solid tumors where they promote invasive tumor growth, intravasation into vasculature and metastasis of malignant cells1,2. Fibroblasts, on the other hand, lead collective cell migration3 of carcinoma cells via fostering extracellular matrix (ECM) remodeling and generating tracks of collagen fibers that act as “highways” for cell migration4,5. To identify soluble molecules mediating these juxtacrine communication mechanisms between myeloid cells and fibroblasts in potentiating metastasis, we conducted pilot studies with subsets of spleen- or tumor-derived myeloid cells, tumor-derived fibroblasts, and mammary adenocarcinoma cells. Whereas spleen-derived CD11b+Ly6ChiLy6G− monocytes promote fibroblast migration ex vivo, two populations of tumor-derived myeloid cells, e.g., CD11b+Gr1+ and CD11b+Gr1− cells possessed this capability. In ex vivo migration assays, fibroblast migration was dependent on myeloid cell-derived factors, e.g., CXCL11, CXCL15, FGF2, IGF-1 and Shh, as well as fibroblast Akt and ERK1/2 phosphorylation. Inhibition of fibroblast MEK reduced myeloid cell-induced fibroblast migration, whereas FGF-RI inhibition completely abolished this capability. These studies indicate a role for myeloid cell-fibroblast communication in fostering migration (and potentially activation) of fibroblasts that lead collective cell migration properties of mammary carcinoma cells. Ongoing studies are identifying specific subpopulations of tumor-associated myeloid cells possessing these activities, as well as the role of FGF receptor signaling pathways in facilitating metastasis. 1. Wyckoff, J.B., et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 67, 2649-2656 (2007). 2. Qian, B.Z. & Pollard, J.W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39-51 (2010). 3. Friedl, P., Locker, J., Sahai, E. & Segall, J.E. Classifying collective cancer cell invasion. Nat Cell Biol 14, 777-783 (2012). 4. Khalil, A.A. & Friedl, P. Determinants of leader cells in collective cell migration. Integr Biol (Camb) 2, 568-574 (2010). 5. Gritsenko, P.G., Ilina, O. & Friedl, P. Interstitial guidance of cancer invasion. J Pathol 226, 185-199 (2012). The authors acknowledge generous support from the NIH/NCI, a Dept of Defense (DoD) Breast Cancer Research Program Postdoctoral Fellowship, a DoD Era of Hope Scholar Expansion Award, Susan G. Komen Fndt, and the Breast Cancer Research Fndt. Citation Format: Aubie K. Shaw, Sergey Novitskiy, Lisa M. Coussens, Harold L. Moses. Myeloid cells promote fibroblast invasion and lead mammary adenocarcinoma cell invasion. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2301. doi:10.1158/1538-7445.AM2013-2301