Vascular Control of Organ Function
Vascular control of adipose tissue and consequences for tumor progression
Angiocrine signaling is a key regulator of organ development and regeneration, but still little is known about its roles in disease conditions. This project addresses how the quiescent endothelium responds to disease conditions and how this alters expression of angiocrine factors and subsequently disease progression. Work during the first funding period showed how cancer and metabolic changes alter endothelial transcriptomes in metabolic highly active organs. Modelling such endothelial-specific changes in mice revealed that Notch1-driven angiocrine signals control metabolism in muscle and adipose tissue and strongly contribute to tumor progression. We therefore propose that the endothelium is a mediator or even an amplifier of cancer-released factors.
The experimental program of the second funding period will systematically unravel how cancer changes endothelial heterogeneity and the angiocrine landscape and to decipher how angiocrine signaling contributes to tissue wasting during tumor progression. We will explore endothelial heterogeneity in white adipose tissue and explore how metabolic alterations or the presence of a solid tumor mass at distant sites changes endothelial heterogeneity and function. We will decipher how cachectokines act across long-distance on the endothelium and how this contributes to tissue wasting. Ultimately, we aim at developing therapeutical strategies to interfere with the cancer-endothelial crosstalk to delay the onset of metastasis and cancer cachexia.