Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia

Jacqueline Taylor, Leonie Uhl, Iris Moll, Sana Safatul Hasan, Lena Wiedmann, Jakob Morgenstern, Benedetto Daniele Giaimo, Tobias Friedrich, Elisenda Alsina-Sanchis, Francesca De Angelis Rigotti, Ronja Mülfarth, Sarah Kaltenbach, Darius Schenk, Felix Nickel, Thomas Fleming, David Sprinzak, Carolin Mogler, Thomas Korff, Adrian T. Billeter, Beat P. Müller-StichMauricio Berriel Diaz, Tilman Borggrefe, Stephan Herzig, Maria Rohm, Juan Rodriguez-Vita*, Andreas Fischer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Cachexia is a major cause of morbidity and mortality in individuals with cancer and is characterized by weight loss due to adipose and muscle tissue wasting. Hallmarks of white adipose tissue (WAT) remodeling, which often precedes weight loss, are impaired lipid storage, inflammation and eventually fibrosis. Tissue wasting occurs in response to tumor-secreted factors. Considering that the continuous endothelium in WAT is the first line of contact with circulating factors, we postulated whether the endothelium itself may orchestrate tissue remodeling. Here, we show using human and mouse cancer models that during precachexia, tumors overactivate Notch1 signaling in distant WAT endothelium. Sustained endothelial Notch1 signaling induces a WAT wasting phenotype in male mice through excessive retinoic acid production. Pharmacological blockade of retinoic acid signaling was sufficient to inhibit WAT wasting in a mouse cancer cachexia model. This demonstrates that cancer manipulates the endothelium at distant sites to mediate WAT wasting by altering angiocrine signals.

Original languageEnglish
Pages (from-to)1544-1560
Number of pages17
JournalNature Cancer
Volume4
Issue number11
DOIs
StatePublished - Nov 2023

Funding

FundersFunder number
Behring-Röntgen foundation
LOEWE
MasQueUnTrail Association
Niedersachsen-Israel Forschungskooperation11-76251-4653/2022 ZN4036
Proteomics Core Facility
University Medical Center Giessen and Marburg
Deutsches Krebsforschungszentrum
Justus Liebig Universität Gießen
Deutsche ForschungsgemeinschaftSFB1118-A04/S01, BO 1639/9-1, 394046768-SFB1366, TRR81-A12
Asociación Española de Investigación sobre el CáncerPID2020-117946GB-I00, MCIN/AEI/10.13039/501100011033, RYC2019-027937-I

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