Apelin-driven endothelial cell migration sustains intestinal progenitor cells and tumor growth

Stem and progenitor cells residing in the intestinal crypts drive the majority of colorectal cancers (CRCs), yet vascular contribution to this niche remains largely unexplored. Vascular endothelial growth factor A (VEGFA) is a key driver of physiological and tumor angiogenesis. Accordingly, current anti-angiogenic cancer therapies target the VEGFA pathway. Here we report that in CRC expansion of the stem/progenitor pool in intestinal crypts requires VEGFA-independent growth and remodeling of blood vessels. Epithelial transformation-induced expression of the endothelial peptide apelin, directs migration of distant venous endothelial cells toward progenitor niche vessels ensuring optimal perfusion. In the absence of apelin, loss of injury-inducible PROX1+ epithelial progenitors inhibited both incipient and advanced intestinal tumor growth. Our results establish fundamental principles for the reciprocal communication between vasculature and the intestinal progenitor niche and provide a mechanism for resistance to VEGFA-targeting drugs in CRCs. Bernier-Latmani et al. report a mechanism for maintaining colon cancer-associated vasculature, in which colon endothelial apelin signaling promotes migration of distant venous endothelial cells toward the tumor progenitor cell niche to sustain VEGFA-independent vascular expansion and a normoxic microenvironment.