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

פרסום מחקרי: פרסום בכתב עתמאמרביקורת עמיתים


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.

שפה מקוריתאנגלית
עמודים (מ-עד)1544-1560
מספר עמודים17
כתב עתNature Cancer
מספר גיליון11
מזהי עצם דיגיטלי (DOIs)
סטטוס פרסוםפורסם - נוב׳ 2023

ASJC Scopus subject areas

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