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Kaltenecker, D. ; Schmidt, S.F. ; Weber, P. ; Loft, A. ; Morigny, P. ; Machado, J. ; Geppert, J. ; Saul, K.B.* ; Benedikt-Kühnast, P. ; Molocea, C.-E. ; Scott, R.* ; Haase, K.* ; Martignoni, M.E.* ; Alfaro, A.J. ; Chow, K.K. ; Simoes Fernandez, E. ; Pinhata Otoch, J.* ; Lima, J.D.C.C.* ; Swanton, C.* ; Spielmann, N. ; Hrabě de Angelis, M. ; Elsner, M. ; Ertürk, A. ; Dyar, K.A. ; Rohm, M. ; Prokopchuk, O.* ; Jamal-Hanjani, M.* ; Seelaender, M.* ; Backs, J.* ; Herzig, S. ; Berriel Diaz, M.

Functional liver genomics identifies hepatokines promoting wasting in cancer cachexia.

Cell 188, 4549-4566.e22 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
In cancer cachexia, the presence of a tumor triggers systemic metabolic disruption that leads to involuntary body weight loss and accelerated mortality in affected patients. Here, we conducted transcriptomic and epigenomic profiling of the liver in various weight-stable cancer and cancer cachexia models. An integrative multilevel analysis approach identified a distinct gene expression signature that included hepatocyte-secreted factors and the circadian clock component REV-ERBα as key modulator of hepatic transcriptional reprogramming in cancer cachexia. Notably, hepatocyte-specific genetic reconstitution of REV-ERBα in cachexia ameliorated peripheral tissue wasting. This improvement was associated with decreased levels of specific cachexia-controlled hepatocyte-secreted factors. These hepatokines promoted catabolism in multiple cell types and were elevated in cachectic cancer patients. Our findings reveal a mechanism by which the liver contributes to peripheral tissue wasting in cancer cachexia, offering perspectives for future therapeutic interventions.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Intact ; Rev-erb ; Adipose Tissue Wasting ; Cachexia ; Circadian Clock ; Hepatic Reprogramming ; Liver-secreted Factors ; Muscle Atrophy; Rev-erb-alpha; Gene-expression; Lung-cancer; Transcription; Metabolism; Dysfunction; Mediators; Evolution; Impact; Model
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Zeitschrift Cell
Quellenangaben Band: 188, Heft: 17, Seiten: 4549-4566.e22 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort Cambridge, Mass.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)
Institute of Experimental Genetics (IEG)
Institute for Tissue Engineering and Regenerative Medicine (ITERM)
Förderungen NIHR University College London Hospitals Biomedical Research Centre
Cancer Research UK
UCL Cancer Trials Centre
CRUK
CANCAN Cancer Grand Challenges partnership - Cancer Research UK
NIH National Cancer Institute
CRUK Career Establishment Awardee
NIH National Cancer Institute, IASLC International Lung Cancer Foundation, Lung Cancer Research Foundation
Rosetrees Trust
University College London