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Endothelial Notch1 Signaling in White Adipose Tissue Promotes Cancer Cachexia

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.
Jacqueline Taylor,1 Leonie Uhl,1,2 Iris Moll,1 Sana Safatul Hasan,1,3 Lena Wiedmann,1 Jakob Morgenstern,4 Benedetto Daniele Giaimo,5 Tobias Friedrich,5,6 Elisenda Alsina-Sanchis,1,3 Francesca De Angelis Rigotti,1,7 Ronja Mülfarth,1 Sarah Kaltenbach,3 Darius Schenk,1 Felix Nickel,8 Thomas Fleming,4,9 David Sprinzak,10 Carolin Mogler,11 Thomas Korff,12,13 Adrian T Billeter,8 Beat P Müller-Stich,8 Mauricio Berriel Diaz,14,15, Tilman Borggrefe,5 Stephan Herzig,14,15,16 Maria Rohm,14,15 Juan Rodriguez-Vita,17,18 Andreas Fischer,19,20,21

  1. Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  2. Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Würzburg, Germany.
  3. Department of Clinical Chemistry, University Medical Center Göttingen, Göttingen, Germany.
  4. Department of Internal Medicine Endocrinology and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany.
  5. Institute of Biochemistry, University of Giessen, Giessen, Germany.
  6. Biomedical Informatics and Systems Medicine, Science Unit for Basic and Clinical Medicine, Giessen, Germany.
  7. Tumor-Stroma Communication Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain.
  8. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
  9. German Center of Diabetes Research (DZD), Neuherberg, Germany.
  10. School of Neurobiology, Biochemistry and Biophysics, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
  11. Institute of Pathology, Technical University of Munich School of Medicine, Technical University of Munich, Munich, Germany.
  12. Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, University of Heidelberg, Heidelberg, Germany.
  13. European Center for Angioscience (ECAS), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
  14. Institute for Diabetes and Cancer, Helmholtz Center Munich, German Center for Diabetes Research (DZD), Neuherberg, Germany.
  15. Joint Heidelberg-IDC Translational Diabetes Unit, Department of Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany.
  16. Chair Molecular Metabolic Control, Technical University of Munich, Munich, Germany.
  17. Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  18. Tumor-Stroma Communication Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain.
  19. Division Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  20. Department of Clinical Chemistry, University Medical Center Göttingen, Göttingen, Germany.
  21. German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany.
Source: Taylor J et al. November4, 2023. Endothelial notch1 signaling in white adipose tissue promotes cancer cachexia, Nature cancer.