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Tumor Cytokine-Induced Hepatic Gluconeogenesis Contributes to Cancer Cachexia: Insights from Full Body Single Nuclei Sequencing

A primary cause of death in cancer patients is cachexia, a wasting syndrome attributed to tumor-induced metabolic dysregulation. Despite the major impact of cachexia on the treatment, quality of life, and survival of cancer patients, relatively little is known about the underlying pathogenic mechani...

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Autores principales: Liu, Ying, Dantas, Ezequiel, Ferrer, Miriam, Liu, Yifang, Comjean, Aram, Davidson, Emma E., Hu, Yanhui, Goncalves, Marcus D., Janowitz, Tobias, Perrimon, Norbert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245574/
https://www.ncbi.nlm.nih.gov/pubmed/37292804
http://dx.doi.org/10.1101/2023.05.15.540823
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author Liu, Ying
Dantas, Ezequiel
Ferrer, Miriam
Liu, Yifang
Comjean, Aram
Davidson, Emma E.
Hu, Yanhui
Goncalves, Marcus D.
Janowitz, Tobias
Perrimon, Norbert
author_facet Liu, Ying
Dantas, Ezequiel
Ferrer, Miriam
Liu, Yifang
Comjean, Aram
Davidson, Emma E.
Hu, Yanhui
Goncalves, Marcus D.
Janowitz, Tobias
Perrimon, Norbert
author_sort Liu, Ying
collection PubMed
description A primary cause of death in cancer patients is cachexia, a wasting syndrome attributed to tumor-induced metabolic dysregulation. Despite the major impact of cachexia on the treatment, quality of life, and survival of cancer patients, relatively little is known about the underlying pathogenic mechanisms. Hyperglycemia detected in glucose tolerance test is one of the earliest metabolic abnormalities observed in cancer patients; however, the pathogenesis by which tumors influence blood sugar levels remains poorly understood. Here, utilizing a Drosophila model, we demonstrate that the tumor secreted interleukin-like cytokine Upd3 induces fat body expression of Pepck1 and Pdk, two key regulatory enzymes of gluconeogenesis, contributing to hyperglycemia. Our data further indicate a conserved regulation of these genes by IL-6/JAK-STAT signaling in mouse models. Importantly, in both fly and mouse cancer cachexia models, elevated gluconeogenesis gene levels are associated with poor prognosis. Altogether, our study uncovers a conserved role of Upd3/IL-6/JAK-STAT signaling in inducing tumor-associated hyperglycemia, which provides insights into the pathogenesis of IL-6 signaling in cancer cachexia.
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spelling pubmed-102455742023-06-08 Tumor Cytokine-Induced Hepatic Gluconeogenesis Contributes to Cancer Cachexia: Insights from Full Body Single Nuclei Sequencing Liu, Ying Dantas, Ezequiel Ferrer, Miriam Liu, Yifang Comjean, Aram Davidson, Emma E. Hu, Yanhui Goncalves, Marcus D. Janowitz, Tobias Perrimon, Norbert bioRxiv Article A primary cause of death in cancer patients is cachexia, a wasting syndrome attributed to tumor-induced metabolic dysregulation. Despite the major impact of cachexia on the treatment, quality of life, and survival of cancer patients, relatively little is known about the underlying pathogenic mechanisms. Hyperglycemia detected in glucose tolerance test is one of the earliest metabolic abnormalities observed in cancer patients; however, the pathogenesis by which tumors influence blood sugar levels remains poorly understood. Here, utilizing a Drosophila model, we demonstrate that the tumor secreted interleukin-like cytokine Upd3 induces fat body expression of Pepck1 and Pdk, two key regulatory enzymes of gluconeogenesis, contributing to hyperglycemia. Our data further indicate a conserved regulation of these genes by IL-6/JAK-STAT signaling in mouse models. Importantly, in both fly and mouse cancer cachexia models, elevated gluconeogenesis gene levels are associated with poor prognosis. Altogether, our study uncovers a conserved role of Upd3/IL-6/JAK-STAT signaling in inducing tumor-associated hyperglycemia, which provides insights into the pathogenesis of IL-6 signaling in cancer cachexia. Cold Spring Harbor Laboratory 2023-05-18 /pmc/articles/PMC10245574/ /pubmed/37292804 http://dx.doi.org/10.1101/2023.05.15.540823 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Liu, Ying
Dantas, Ezequiel
Ferrer, Miriam
Liu, Yifang
Comjean, Aram
Davidson, Emma E.
Hu, Yanhui
Goncalves, Marcus D.
Janowitz, Tobias
Perrimon, Norbert
Tumor Cytokine-Induced Hepatic Gluconeogenesis Contributes to Cancer Cachexia: Insights from Full Body Single Nuclei Sequencing
title Tumor Cytokine-Induced Hepatic Gluconeogenesis Contributes to Cancer Cachexia: Insights from Full Body Single Nuclei Sequencing
title_full Tumor Cytokine-Induced Hepatic Gluconeogenesis Contributes to Cancer Cachexia: Insights from Full Body Single Nuclei Sequencing
title_fullStr Tumor Cytokine-Induced Hepatic Gluconeogenesis Contributes to Cancer Cachexia: Insights from Full Body Single Nuclei Sequencing
title_full_unstemmed Tumor Cytokine-Induced Hepatic Gluconeogenesis Contributes to Cancer Cachexia: Insights from Full Body Single Nuclei Sequencing
title_short Tumor Cytokine-Induced Hepatic Gluconeogenesis Contributes to Cancer Cachexia: Insights from Full Body Single Nuclei Sequencing
title_sort tumor cytokine-induced hepatic gluconeogenesis contributes to cancer cachexia: insights from full body single nuclei sequencing
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245574/
https://www.ncbi.nlm.nih.gov/pubmed/37292804
http://dx.doi.org/10.1101/2023.05.15.540823
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