KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis

Abstract

A deeper understanding of the metastatic process is required for the development of new therapies that improve patient survival. Metastatic tumor cell growth and survival in distant organs is facilitated by the formation of a pre-metastatic niche composed of hematopoietic cells, stromal cells, and extracellular matrix (ECM). Perivascular cells, including vascular smooth muscle cells (vSMCs) and pericytes, are involved in new vessel formation and in promoting stem cell maintenance and proliferation. Given the well-described plasticity of perivascular cells, we hypothesize that perivascular cells similarly regulate tumor cell fate at metastatic sites. Using perivascular cell-specific and pericyte-specific lineage-tracing models, we trace the fate of perivascular cells in the pre-metastatic and metastatic microenvironments. We show that perivascular cells lose the expression of traditional vSMC/pericyte markers in response to tumor-secreted factors and exhibit increased proliferation, migration, and ECM synthesis. Increased expression of the pluripotency gene Klf4 in these phenotypically-switched perivascular cells promotes a less differentiated state characterized by enhanced ECM production that establishes a pro-metastatic fibronectin-rich environment. Genetic inactivation of Klf4 in perivascular cells decreases pre-metastatic niche formation and metastasis. Our data reveal a previously unidentified role for perivascular cells in pre-metastatic niche formation and uncover novel strategies for limiting metastasis.

Disease-relevant single cell photonic signatures identify S100β stem cells and their myogenic progeny in vascular lesions

“…Although the Myh11-CreERT2 transgene was originally deemed specific for vascular SMC 71 , data indicating expression of this and other SMC differentiation genes in non-SMC populations has recently emerged raising the possibility that other resident cells may contribute to lesion formation [72][73][74] .…”

Tumor microenvironment complexity and therapeutic implications at a glance

“…Current strategies may lack sufficient specificity due to targeting of whole population of pericytes. A better understanding of the molecular mechanisms of tumor progression involving pericytes may reveal specific targets within pericyte subpopulations and thus contributes to cancer treatments [36]. This can be achieved in part by using microfluidic systems that can recapitulate more complex biological interfaces that would otherwise be unattainable by two-dimensional (2D) systems to study the dynamic interaction of pericytes with different TME components under normal or pathological conditions.…”

Metastatic niche functions and therapeutic opportunities

“…Review ARticle | SERIES NaTure Cell Biology production to generate a pre-metastatic niche rich in fibronectin, favouring the ensuing metastasis 38 . This is similar to the fibroblast-secreted fibronectin in earlier reports of pre-metastatic niches 12 .…”