Fard, Damon, Pirani, Edisa, Gomez-Jenkins, Maria, Lopez-Darwin, Sereno, Ibrahim, Maria, Schell, Lilia, Larkin, Charlotte, Gorgui, Clara, Berdasco, Clara, Hu, Zhixian, Das, Trishna, Powers, Jesse, Anthony, Tracy G, Rabinowitz, Joshua D, Raphael, Benjamin J, Guo, Jessie Yanxiang, Goncalves, Marcus D, Janowitz, Tobias, White, Eileen (October 2026) Behavioral dysfunction but not wasting in cancer cachexia is driven by altered tryptophan metabolism. bioRxiv. ISSN 2692-8205 (Submitted)
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Abstract
Cancer cachexia causes pathological weight loss, anorexia, and depressive symptoms, culminating in increased mortality. Using mouse models of pancreatic cancer cachexia, we identify tumor and hepatic inflammatory signaling, multi-organ energy charge depletion, and altered tryptophan metabolism. Metabolomic profiling and stable isotope tracing revealed altered tryptophan fates: serotonin depletion and kynurenine accumulation across tumor, liver, muscle and spleen. Kynurenine accumulation involved accelerated conversion of tryptophan to kynurenine with slowed downstream conversion to kynurenic acid. Restoring serotonin activity pharmacologically or metabolically normalized feeding, locomotion, and depression-like behavior, but wasting, tumor burden, and survival remained unchanged. Blocking kynurenine production or kynurenine-mediated AhR activation pharmacologically produced similar results. Thus, in cancer cachexia, the tryptophan pathway is subverted to deplete serotonin and accumulate kynurenine. This subversion contributes to cachexia-associated behavioral and feeding defects but not lethal systemic catabolism.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders diseases & disorders > nutritional and metabolic diseases diseases & disorders > nutritional and metabolic diseases > cachexia |
| CSHL Authors: | |
| Communities: | CSHL labs > Janowitz lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 9 October 2026 |
| Date Deposited: | 06 Nov 2026 18:56 |
| Last Modified: | 06 Nov 2026 18:56 |
| PMCID: | PMC13692228 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/42363 |
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