Behavioral dysfunction but not wasting in cancer cachexia is driven by altered tryptophan metabolism
- 1Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA; Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University,
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.
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BibTeX
@misc{fard2026behavioral,
title = {{Behavioral dysfunction but not wasting in cancer cachexia is driven by altered tryptophan metabolism}},
author = {D. Fard and E. Pirani and M. Gomez-Jenkins and S. Lopez-Darwin and M. Ibrahim and L. Schell and C. Larkin and C. Gorgui and C. Berdasco and Z. Hu and T. Das and J. Powers and T. G. Anthony and J. D. Rabinowitz and B. J. Raphael and J. Y. Guo and M. D. Goncalves and T. Janowitz and E. White},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.08.757616},
url = {https://www.biorxiv.org/content/10.64898/2026.10.08.757616v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Behavioral dysfunction but not wasting in cancer cachexia is driven by altered tryptophan metabolism
AU - D. Fard
AU - E. Pirani
AU - M. Gomez-Jenkins
AU - S. Lopez-Darwin
AU - M. Ibrahim
AU - L. Schell
AU - C. Larkin
AU - C. Gorgui
AU - C. Berdasco
AU - Z. Hu
AU - T. Das
AU - J. Powers
AU - T. G. Anthony
AU - J. D. Rabinowitz
AU - B. J. Raphael
AU - J. Y. Guo
AU - M. D. Goncalves
AU - T. Janowitz
AU - E. White
PY - 2026
DA - 2026/10/08
PB - bioRxiv
DO - 10.64898/2026.10.08.757616
UR - https://www.biorxiv.org/content/10.64898/2026.10.08.757616v1
AB - 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.
ER -