Biology subjects

Fard, D.

Publications and source records attributed to Fard, D..

3 recordsLinked to original sources

bioRxiv2026

Behavioral dysfunction but not wasting in cancer cachexia is driven by altered tryptophan metabolism

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.

cancer biology↗

bioRxiv2026

Engaging the host adaptive response to nutrient limitation delays cancer cachexia

Cancer cachexia is a debilitating wasting syndrome associated with involuntary weight loss, reduced appetite and food intake, adipose and muscle atrophy, and systemic inflammation with induction of a myriad of candidate cachexia factors. Using a multi-omic approach in a genetically engineered mouse model of lung cancer cachexia, we found that early circulating metabolic alterations preceded overt weight loss. Although both cachexia and fasting are characterized by a reduction in food intake, we show that the systemic metabolic changes in cachexia are distinct, indicating a lack of induction in the normal protective response to negative energy balance during cachexia. Cancer cachexia causes profound hepatic reprogramming, and activation of inflammatory programs, alongside muscle atrophy and elevation of circulating cytokines. However, targeting individual candidate cachectic factors such as IL-6, TNF-, GDF15, CCL2, LIF, and IL17A failed to rescue weight loss or prolong survival. In contrast, caloric restriction initiated prior to tumor induction elicited a program of protection during tumor progression that attenuated multi-tissue inflammatory and catabolic transcriptional responses, preserved lean mass, and prolonged survival. Together, these findings suggest that metabolic preconditioning broadly dampens systemic inflammation and delays the onset and progression of cancer cachexia.

cancer biology↗

bioRxiv2018

Genome-encoded Cytoplasmic Double-Stranded RNAs, Found in C9ORF72 ALS-FTD Brain, Provoke Propagated Neuronal Death

Innate immune signaling activation and DNA damage are pathological hallmarks of aging that may herald multiple adult-onset neurodegenerative diseases. Here, we report that both cell autonomous and non-autonomous neuronal death are triggered by the production of cytoplasmic double-stranded RNA (cdsRNA) from a regulated, disarticulated transgene in the setting of type I interferon (IFN-I) signaling. CdsRNA is a pathogen associated molecular pattern that induces IFN-I in many cell types. Transfection of a dsRNA mimetic into cultured human neurons also induces IFN-I signaling and cell death in a dose-dependent manner. Direct relevance to human disease is found in neurons of ALS-FTD patients carrying C9ORF72 intronic hexanucleotide expansions; cdsRNA isolated from these tissues is comprised of repeat sequences. Together, these findings implicate cdsRNA generated from genomic sequences in neurons as a trigger for sterile, viral-mimetic IFN-I induction and propagated neuronal death within in a neural circuit in the aging nervous system.

neuroscience↗