๐ค Authors: Doris Kaltenecker, Sรธren Fisker Schmidt, Peter Weber, Anne Loft, Pauline Morigny, Juliano Machado, Julia Geppert, Kerstin Beate Saul, Pia Benedikt, Claudia-Eveline Molocea, Rachel Scott, Kerstin Haase, Marc E Martignoni, Ana Jimena Alfaro, Kan Kau Chow, Estefania Simoes, Josรฉ Pinhata Otoch, Joanna D C C Lima, Charles Swanton, Nadine Spielmann, Martin Hrabรฉ de Angelis, Markus Elsner, Ali Ertรผrk, Kenneth A Dyar, Maria Rohm, Olga Prokopchuk, Mariam Jamal-Hanjani, Marilia Seelaender, Johannes Backs, Stephan Herzig, Mauricio Berriel Diaz
Functional liver genomics identifies hepatokines promoting wasting in cancer cachexia.
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-ERBฮฑ as key modulator of hepatic transcriptional reprogramming in cancer cachexia. Notably, hepatocyte-specific genetic reconstitution of REV-ERBฮฑ 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.
