Notch1 Signaling in the White Adipose Tissue Endothelium Promotes Cachexia

Cachexia is a multifactorial wasting syndrome that affects many patients with advanced cancer, but treatments for this condition are lacking. Remodeling of the white adipose tissue (WAT) can be detected in patients during the precachectic state, but how tumor-secreted factors that promote this tissue wasting affect the continuous endothelium in WAT, which provides the first line of contact to these factors, is not yet known. In this study, Taylor and colleagues sought to determine how distant tumors alter the angiocrine landscape of endothelial cells in adipose tissue to induce WAT remodeling and showed that Notch1 signaling in the WAT endothelium is overactivated during precachexia in both humans and mice due to tumor cell secretion of proinflammatory cytokines, including TNFα. This sustained Notch1 signaling in adipose tissue endothelial cells (AT-EC) induced WAT remodeling in a sex-specific manner, with male mice demonstrating a more robust phenotype than female mice. Moreover, apoptosis, beiging, type II inflammation, and fibrosis were increased over the course of cachexia in a well-characterized Notch1 gain-of-function mouse, mimicking the hallmarks of this disease. Mechanistically, ALDH1-mediated production of retinoic acid (RA) is induced by AT-EC Notch1 signaling, with IL33-dependent mechanisms also potentiating whole-tissue RA production by acting on both macrophages and adipocytes. This enhanced production of RA subsequently leads to cachectic WAT loss through induction of UCP1 expression, a thermogenic protein, as well as the proapoptotic protein IGFBP3. Furthermore, pharmacologically inhibiting RA using the pan-RA receptor oral antagonist BMS493 demonstrated inhibition of WAT wasting and alterations to adipocyte size with no difference in tumor mass in a murine pancreatic cancer cachexia model. In summary, the results of this study show that Notch1 signaling is a major regulator of tumor-induced WAT remodeling and loss and suggest that RA signaling downstream of Notch1 could be a targetable pathway to prevent the morbidity and mortality associated with cancer cachexia.

Taylor J, Uhl L, Moll I, Hasan SS, Wiedmann L, Morgenstern J, et al. Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia. Nat Cancer 2023 Sep 25 [Epub ahead of print].

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