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Publication : Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia.

First Author  Taylor J Year  2023
Journal  Nat Cancer Volume  4
Issue  11 Pages  1544-1560
PubMed ID  37749321 Mgi Jnum  J:343090
Mgi Id  MGI:7562639 Doi  10.1038/s43018-023-00622-y
Citation  Taylor J, et al. (2023) Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia. Nat Cancer 4(11):1544-1560
abstractText  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.
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