Abstract 4050: A central role for mTORC1 in CXCR4-mediated directional migration and metastasis

Tumor cells can co-opt the promigratory activity of chemokines and their cognate G protein-coupled receptors to disseminate to regional lymph nodes and distant organs. Indeed, the migration to SDF-1 of tumor cells expressing its receptor, CXCR4, is implicated in lymphatic and organ-specific metastasis in multiple human malignancies. However, the critical role of CXCR4 in bone marrow stem cell retention has hampered the development of CXCR4 inhibitors for metastasis prevention. Therefore the study of CXCR4 downstream signaling circuitry may provide new opportunities for the treatment of many human malignancies that depend on CXCR4 for their metastatic spread. The PI3K/mTOR pathway represents a major player in normal and aberrant cell growth. Consistently, mTOR inhibitors targeting its complex 1 (mTORC1) alone or mTORC1/mTORC2 have already shown promising therapeutic responses in many tumor types. Our data show that mTOR is activated upon SDF-1 stimulation of CXCR4 on epithelial-derived cancer cells, and that the disruption of mTORC1 or mTORC2 abrogates CXCR4-mediated directional migration. To study the CXCR4/mTOR axis in vivo we developed a simple and robust model for CXCR4-mediated spontaneous metastasis. Surprisingly, disruption of mTORC1 alone was sufficient to decrease tumor cell proliferation, angiogenesis, lymphangiogenesis, and CXCR4-mediated metastasis, whereas mTORC2 impairment had no effect on tumor dissemination or growth in vivo. Taken together, our data suggest that mTORC1 blockade could inhibit the migration of CXCR4 expressing cancer cells to their secondary sites, while disrupting the establishment of a permissive tumor microenvironment thereby halting the spread of highly aggressive tumors that require CXCR4 to metastasize. Citation Format: Patricia Dillenburg-Pilla, Vyomesh Patel, Constantinos M. Mikelis, Carlos Rodrigo Zarate-Blades, Panomwat Amornphimoltham, Zhiyong Wang, Daniel Martin, Kantima Leelahavanichkul, Colleen L. Doci, Robert T. Dorsam, Andrius Masedunskas, Nijiro Nohata , Roberto Weigert, Alfredo A. Molinolo, J. Silvio Gutkind . A central role for mTORC1 in CXCR4-mediated directional migration and metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4050. doi:10.1158/1538-7445.AM2014-4050