Perivascular plasticity in metastatic microenvironments

Division Of Basic Sciences - Nci

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Abstract

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 growth in distant organ sites is facilitated by premetastatic niche formation, which is composed of hematopoietic cells, stromal cells, and extracellular matrix that support tumor survival and growth. Perivascular cells, including Myh11+ vascular smooth muscle cells (vSMCs) and NG2+ pericytes, are a key cell population involved in new blood vessel formation critical to primary tumor pathogenesis. Using multiple perivascular cell-specific lineage tracing models, we have recently demonstrated that perivascular cells are phenotypically switched within premetastatic tissue whereby they lose the expression of traditional perivascular markers in response to tumor-secreted factors (Murgai et al., 2017). Expression of the pluripotency transcription factor KLF4 is increased in these perivascular cells and mediates a transition to a less differentiated state characterized by increased proliferation and extracellular matrix (ECM) production. Genetic inactivation of KLF4 in perivascular cells decreases pre-metastatic niche formation and consequently metastasis. These data reveal a previously unidentified role for perivascular cells in pre-metastatic niche formation and highlights a critical need for a deeper understanding of these cell types and their behavior in this process for the development of therapeutic strategies that modulate stromal cell plasticity for limiting metastasis. We are currently addressing this problem through two approaches: 1. Determine the epigenetic role for perivascular cell KLF4 and Oct4 expression in metastatic niches; and 2. Determine the KLF4/Oct4-dependent recruitment and pathogenic contribution of NG2+ and PDGFRa+ stromal cells to metastatic niches.