Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia.

Fecha de publicación: Fecha Ahead of Print:

Autores de CIPF

Participantes ajenos a CIPF

  • Taylor J
  • Uhl L
  • Moll I
  • Hasan SS
  • Wiedmann L
  • Morgenstern J
  • Giaimo BD
  • Friedrich T
  • Alsina-Sanchis E
  • Mülfarth R
  • Kaltenbach S
  • Schenk D
  • Nickel F
  • Fleming T
  • Sprinzak D
  • Mogler C
  • Korff T
  • Billeter AT
  • Müller-Stich BP
  • Berriel Diaz M
  • Borggrefe T
  • Herzig S
  • Rohm M
  • Fischer A

Grupos de Investigación

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.

Datos de la publicación

ISSN/ISSNe:
2662-1347, 2662-1347

Nature Cancer  NATURE PORTFOLIO

Tipo:
Article
Páginas:
1544-1560
PubMed:
37749321

Citas Recibidas en Web of Science: 12

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