Klf4-Dependent Perivascular Plasticity Enhances Pre-Metastatic Niche Formation And Metastasis

Metastasis causes most cancer deaths, and new therapies that are based on a deeper understanding of this process are required to improve patient survival. Metastatic tumor cell colonization and growth is facilitated by a pre-metastatic niche microenvironment composed of hematopoietic cells, stromal cells, and extracellular matrix that support tumor survival and growth. Perivascular cells, including vascular smooth muscle cells (vSMCs) and pericytes, are a key cell population involved in new vessel formation critical to primary tumor development. Given the well-described plasticity of perivascular cells, we sought to determine whether perivascular cells regulate tumor cell survival and proliferation at metastatic sites. Using perivascular cell-specific and pericyte-specific lineage tracing models, we demonstrated that perivascular cells lose traditional vSMC/pericyte marker expression in response to tumor-secreted factors, and exhibit increased proliferation, migration and extracellular matrix (ECM) synthesis. Expression of the pluripotency gene Klf4 is increased and is critical for this phenotypic transition to a less differentiated state characterized by increased proliferation and ECM production. Genetic inactivation of Klf4 specifically in perivascular cells decreases pre-metastatic perivascular cell proliferation and consequently integrin-fibronectin dependent tumor metastasis. Our data reveal a previously unidentified role for perivascular cells in pre-metastatic niche formation, and suggest that modulation of stromal cell plasticity may provide a novel strategy for limiting metastasis. Citation Format: Meera Murgai, Wei Ju, Matthew Eason, Jessica Kline, Rosandra N. Kaplan. KLF4-dependent perivascular plasticity enhances pre-metastatic niche formation and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3914. doi:10.1158/1538-7445.AM2017-3914