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

Prudence Donovan, Jatin Patel (), James Dight, Ho Yi Wong, Seen-Ling Sim, Valentine Murigneux, Mathias Francois and Kiarash Khosrotehrani ()
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Prudence Donovan: The University of Queensland
Jatin Patel: The University of Queensland
James Dight: The University of Queensland
Ho Yi Wong: The University of Queensland
Seen-Ling Sim: The University of Queensland
Valentine Murigneux: The University of Queensland
Mathias Francois: The University of Queensland
Kiarash Khosrotehrani: The University of Queensland

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-07961-w

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