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An integrative pan-cancer investigation reveals common genetic and transcriptional alterations of AMPK pathway genes as important predictors of clinical outcomes across major cancer types
BACKGROUND: The AMP-activated protein kinase (AMPK) is an evolutionarily conserved regulator of cellular energy homeostasis. As a nexus for transducing metabolic signals, AMPK cooperates with other energy-sensing pathways to modulate cellular responses to metabolic stressors. With metabolic reprogra...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433212/ https://www.ncbi.nlm.nih.gov/pubmed/32807122 http://dx.doi.org/10.1186/s12885-020-07286-2 |
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author | Chang, Wai Hoong Lai, Alvina G. |
author_facet | Chang, Wai Hoong Lai, Alvina G. |
author_sort | Chang, Wai Hoong |
collection | PubMed |
description | BACKGROUND: The AMP-activated protein kinase (AMPK) is an evolutionarily conserved regulator of cellular energy homeostasis. As a nexus for transducing metabolic signals, AMPK cooperates with other energy-sensing pathways to modulate cellular responses to metabolic stressors. With metabolic reprogramming being a hallmark of cancer, the utility of agents targeting AMPK has received continued scrutiny and results have demonstrated conflicting effects of AMPK activation in tumorigenesis. Harnessing multi-omics datasets from human tumors, we seek to evaluate the seemingly pleiotropic, tissue-specific dependencies of AMPK signaling dysregulation. METHODS: We interrogated copy number variation and differential transcript expression of 92 AMPK pathway genes across 21 diverse cancers involving over 18,000 patients. Cox proportional hazards regression and receiver operating characteristic analyses were used to evaluate the prognostic significance of AMPK dysregulation on patient outcomes. RESULTS: A total of 24 and seven AMPK pathway genes were identified as having loss- or gain-of-function features. These genes exhibited tissue-type dependencies, where survival outcomes in glioma patients were most influenced by AMPK inactivation. Cox regression and log-rank tests revealed that the 24-AMPK-gene set could successfully stratify patients into high- and low-risk groups in glioma, sarcoma, breast and stomach cancers. The 24-AMPK-gene set could not only discriminate tumor from non-tumor samples, as confirmed by multidimensional scaling analyses, but is also independent of tumor, node and metastasis staging. AMPK inactivation is accompanied by the activation of multiple oncogenic pathways associated with cell adhesion, calcium signaling and extracellular matrix organization. Anomalous AMPK signaling converged on similar groups of transcriptional targets where a common set of transcription factors were identified to regulate these targets. We also demonstrated crosstalk between pro-catabolic AMPK signaling and two pro-anabolic pathways, mammalian target of rapamycin and peroxisome proliferator-activated receptors, where they act synergistically to influence tumor progression significantly. CONCLUSION: Genetic and transcriptional aberrations in AMPK signaling have tissue-dependent pro- or anti-tumor impacts. Pan-cancer investigations on molecular changes of this pathway could uncover novel therapeutic targets and support risk stratification of patients in prospective trials. |
format | Online Article Text |
id | pubmed-7433212 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-74332122020-08-19 An integrative pan-cancer investigation reveals common genetic and transcriptional alterations of AMPK pathway genes as important predictors of clinical outcomes across major cancer types Chang, Wai Hoong Lai, Alvina G. BMC Cancer Research Article BACKGROUND: The AMP-activated protein kinase (AMPK) is an evolutionarily conserved regulator of cellular energy homeostasis. As a nexus for transducing metabolic signals, AMPK cooperates with other energy-sensing pathways to modulate cellular responses to metabolic stressors. With metabolic reprogramming being a hallmark of cancer, the utility of agents targeting AMPK has received continued scrutiny and results have demonstrated conflicting effects of AMPK activation in tumorigenesis. Harnessing multi-omics datasets from human tumors, we seek to evaluate the seemingly pleiotropic, tissue-specific dependencies of AMPK signaling dysregulation. METHODS: We interrogated copy number variation and differential transcript expression of 92 AMPK pathway genes across 21 diverse cancers involving over 18,000 patients. Cox proportional hazards regression and receiver operating characteristic analyses were used to evaluate the prognostic significance of AMPK dysregulation on patient outcomes. RESULTS: A total of 24 and seven AMPK pathway genes were identified as having loss- or gain-of-function features. These genes exhibited tissue-type dependencies, where survival outcomes in glioma patients were most influenced by AMPK inactivation. Cox regression and log-rank tests revealed that the 24-AMPK-gene set could successfully stratify patients into high- and low-risk groups in glioma, sarcoma, breast and stomach cancers. The 24-AMPK-gene set could not only discriminate tumor from non-tumor samples, as confirmed by multidimensional scaling analyses, but is also independent of tumor, node and metastasis staging. AMPK inactivation is accompanied by the activation of multiple oncogenic pathways associated with cell adhesion, calcium signaling and extracellular matrix organization. Anomalous AMPK signaling converged on similar groups of transcriptional targets where a common set of transcription factors were identified to regulate these targets. We also demonstrated crosstalk between pro-catabolic AMPK signaling and two pro-anabolic pathways, mammalian target of rapamycin and peroxisome proliferator-activated receptors, where they act synergistically to influence tumor progression significantly. CONCLUSION: Genetic and transcriptional aberrations in AMPK signaling have tissue-dependent pro- or anti-tumor impacts. Pan-cancer investigations on molecular changes of this pathway could uncover novel therapeutic targets and support risk stratification of patients in prospective trials. BioMed Central 2020-08-17 /pmc/articles/PMC7433212/ /pubmed/32807122 http://dx.doi.org/10.1186/s12885-020-07286-2 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Chang, Wai Hoong Lai, Alvina G. An integrative pan-cancer investigation reveals common genetic and transcriptional alterations of AMPK pathway genes as important predictors of clinical outcomes across major cancer types |
title | An integrative pan-cancer investigation reveals common genetic and transcriptional alterations of AMPK pathway genes as important predictors of clinical outcomes across major cancer types |
title_full | An integrative pan-cancer investigation reveals common genetic and transcriptional alterations of AMPK pathway genes as important predictors of clinical outcomes across major cancer types |
title_fullStr | An integrative pan-cancer investigation reveals common genetic and transcriptional alterations of AMPK pathway genes as important predictors of clinical outcomes across major cancer types |
title_full_unstemmed | An integrative pan-cancer investigation reveals common genetic and transcriptional alterations of AMPK pathway genes as important predictors of clinical outcomes across major cancer types |
title_short | An integrative pan-cancer investigation reveals common genetic and transcriptional alterations of AMPK pathway genes as important predictors of clinical outcomes across major cancer types |
title_sort | integrative pan-cancer investigation reveals common genetic and transcriptional alterations of ampk pathway genes as important predictors of clinical outcomes across major cancer types |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433212/ https://www.ncbi.nlm.nih.gov/pubmed/32807122 http://dx.doi.org/10.1186/s12885-020-07286-2 |
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