Endovascular progenitors infiltrate melanomas and differentiate towards a variety of vascular beds promoting tumor metastasis

Abstract

Tumor vascularization is a hallmark of cancer central to disease progression and metastasis. Current anti-angiogenic therapies have limited success prompting the need to better understand the cellular origin of tumor vessels. Using fate-mapping analysis of endothelial cell populations in melanoma, we report the very early infiltration of endovascular progenitors (EVP) in growing tumors. These cells harbored self-renewal and reactivated the expression of SOX18 transcription factor, initiating a vasculogenic process as single cells, progressing towards a transit amplifying stage and ultimately differentiating into more mature endothelial phenotypes that comprised arterial, venous and lymphatic subtypes within the core of the tumor. Molecular profiling by RNA sequencing of purified endothelial fractions characterized EVPs as quiescent progenitors remodeling the extracellular matrix with significant paracrine activity promoting growth. Functionally, EVPs did not rely on VEGF-A signaling whereas endothelial-specific loss of Rbpj depleted the population and strongly inhibited metastasis. The understanding of endothelial heterogeneity opens new avenues for more effective anti-vascular therapies in cancer.

Aging induces cardiac mesenchymal stromal cell senescence and promotes endothelial cell fate of the CD90 + subset

“…At the molecular level, the CD31+ cMSC subset had strong similarities with endovascular progenitors (EVPs) involved in developing vasculature during wound healing (Patel et al, ) and tumor growth (Donovan et al, ). Similar to CD31+ cMSCs, EVPs express Sca‐1, PDGFRα, CD34 and CD90, as well as low to intermediate levels of endothelial markers.…”

“…Similar to CD31+ cMSCs, EVPs express Sca‐1, PDGFRα, CD34 and CD90, as well as low to intermediate levels of endothelial markers. The generation of ECs from EVPs has been shown to go through a transitional stage, dependent on Notch (Heyl) signaling, but independent on VEGFA signaling (Donovan et al, ). Our microarray data showed that expression of Heyl and Hey1 was reduced in aged cMSCs which could restrain their ability to fully differentiate toward the EC lineage and could explain the increased frequency of CD31+ cMSCs.…”

Single-Cell Transcriptional Profiling of Aortic Endothelium Identifies a Hierarchy from Endovascular Progenitors to Differentiated Cells

“…Previously, we detected EVP progenitors and D differentiated cells in aortic endothelium and tumor tissue using whole-tissue RNA-seq (Donovan et al, 2019;Patel et al, 2017). These populations were shown to express a set of genes that place cells along the continuum of differentiation (Sox9, Il33, and Pdgfra in EVP and Pecam1 and Sox18 in D).…”

Resistance of melanoma cells to anticancer treatment: a role of vascular endothelial growth factor

“…Improvement of diagnostic methods is also a real challenge -they should not only consider genetic differences between tumours in various patients, but also genetic and phenotypic heterogeneity in the same patient and within one tumour as well. Furthermore, recent studies show that in early tumour growth, the endothelial cell population in melanoma includes endovascular progenitors (EVPs) initiating a vasculogenic process, for which anti-VEGF therapy was not sufficient [103]. This finding confirms the importance of understanding endothelial heterogeneity, which opens up new possibilities for more effective anti-vascular therapies in cancer.…”