TY - JOUR
T1 - Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia
AU - Taylor, Jacqueline
AU - Uhl, Leonie
AU - Moll, Iris
AU - Hasan, Sana Safatul
AU - Wiedmann, Lena
AU - Morgenstern, Jakob
AU - Giaimo, Benedetto Daniele
AU - Friedrich, Tobias
AU - Alsina-Sanchis, Elisenda
AU - De Angelis Rigotti, Francesca
AU - Mülfarth, Ronja
AU - Kaltenbach, Sarah
AU - Schenk, Darius
AU - Nickel, Felix
AU - Fleming, Thomas
AU - Sprinzak, David
AU - Mogler, Carolin
AU - Korff, Thomas
AU - Billeter, Adrian T.
AU - Müller-Stich, Beat P.
AU - Berriel Diaz, Mauricio
AU - Borggrefe, Tilman
AU - Herzig, Stephan
AU - Rohm, Maria
AU - Rodriguez-Vita, Juan
AU - Fischer, Andreas
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/11
Y1 - 2023/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85172159927&partnerID=8YFLogxK
U2 - 10.1038/s43018-023-00622-y
DO - 10.1038/s43018-023-00622-y
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C2 - 37749321
AN - SCOPUS:85172159927
SN - 2662-1347
VL - 4
SP - 1544
EP - 1560
JO - Nature Cancer
JF - Nature Cancer
IS - 11
ER -
