Targeting Amino Acid Signaling and Metabolism in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 9019

Special Issue Editors


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Guest Editor
Cancer Research Centre of Lyon, Université Lyon, INSERM 1052, CNRS 5286, 69008 Lyon, France
Interests: GCN2; ER stress; nutritional stress; lung cancer; metabolic dysfunction

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Guest Editor
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, 85 Park Road, Grafton, Auckland 1023, New Zealand
Interests: Tumour hypoxia; HIF-1α; Glutamine Metabolism; Unfolded Protein Response; PERK; ATF4; Cancer Epigenetics

Special Issue Information

Dear Colleagues,

Cancer cells are characterized by an increased uptake and utilization of amino acids (AAs) in order to generate energy and biomass for growth. The essential role of these nutrients in tumor progression has motivated the development of several strategies based on chemo- and molecular targeted therapies, AA-degrading enzymes or dietary intervention to exploit cancer’s AA dependence. However, recent metabolomics-based studies have now highlighted that tumors are deficient in several AA, including glutamine, compared to their normal counterparts and that AA concentrations fluctuate both spatially and temporally within the tumor microenvironment. Indeed, inadequate tumor perfusion and the overexpression of AA-degrading enzymes (e.g. indoleamine-2,3-dioxygenase 1) leads to a heterogenous supply of AAs, resulting in the dysregulation of metabolic pathway activity and a wide spectrum of cellular alterations in malignant, stromal and immune tumor cells. Adaptation to this nutrient-poor microenvironment is orchestrated by a complex molecular network controlled by sensors including mTOR and GCN2, whose activities are additionally dependent on i) the nature of the lacking amino acid, ii) the availability of other metabolites (notably glucose and oxygen) and iii) intrinsic cellular signals. Investigating this multifaceted relationship between the phenotypic modifications triggered by AA deprivation requires the development of relevant preclinical models to reproduce the altered tumor nutritional micromilieu, paired with techniques and instrumentation to analyze these processes.

This Special Issue aims to provide a valuable resource to the scientific community regarding i) the current state-of-the-art concerning the fundamental contribution of amino acid metabolism and related signaling pathways to tumorigenesis; ii) novel findings regarding innovation in technical approaches, preclinical models and therapeutic strategies based on AA manipulation; and iii) a framework for prioritizing unanswered questions and future challenges concerning AA metabolism in tumors.

Dr. Cedric Chaveroux
Dr. Dean C. Singleton
Guest Editors

Manuscript Submission Information

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Published Papers (2 papers)

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Research

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16 pages, 1839 KiB  
Article
Plasma Metabolomics for Discovery of Early Metabolic Markers of Prostate Cancer Based on Ultra-High-Performance Liquid Chromatography-High Resolution Mass Spectrometry
by Xiangping Lin, Lucie Lécuyer, Xinyu Liu, Mohamed N. Triba, Mélanie Deschasaux-Tanguy, Aïcha Demidem, Zhicheng Liu, Tony Palama, Adrien Rossary, Marie-Paule Vasson, Serge Hercberg, Pilar Galan, Philippe Savarin, Guowang Xu and Mathilde Touvier
Cancers 2021, 13(13), 3140; https://doi.org/10.3390/cancers13133140 - 23 Jun 2021
Cited by 10 | Viewed by 3355
Abstract
Background: The prevention and early screening of PCa is highly dependent on the identification of new biomarkers. In this study, we investigated whether plasma metabolic profiles from healthy males provide novel early biomarkers associated with future risk of PCa. Methods: Using the Supplémentation [...] Read more.
Background: The prevention and early screening of PCa is highly dependent on the identification of new biomarkers. In this study, we investigated whether plasma metabolic profiles from healthy males provide novel early biomarkers associated with future risk of PCa. Methods: Using the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) cohort, we identified plasma samples collected from 146 PCa cases up to 13 years prior to diagnosis and 272 matched controls. Plasma metabolic profiles were characterized using ultra-high-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Results: Orthogonal partial least squares discriminant analysis (OPLS-DA) discriminated PCa cases from controls, with a median area under the receiver operating characteristic curve (AU-ROC) of 0.92 using a 1000-time repeated random sub-sampling validation. Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) identified the top 10 most important metabolites (p < 0.001) discriminating PCa cases from controls. Among them, phosphate, ethyl oleate, eicosadienoic acid were higher in individuals that developed PCa than in the controls during the follow-up. In contrast, 2-hydroxyadenine, sphinganine, L-glutamic acid, serotonin, 7-keto cholesterol, tiglyl carnitine, and sphingosine were lower. Conclusion: Our results support the dysregulation of amino acids and sphingolipid metabolism during the development of PCa. After validation in an independent cohort, these signatures may promote the development of new prevention and screening strategies to identify males at future risk of PCa. Full article
(This article belongs to the Special Issue Targeting Amino Acid Signaling and Metabolism in Cancer)
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Review

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15 pages, 1164 KiB  
Review
The Kynurenine Pathway and Cancer: Why Keep It Simple When You Can Make It Complicated
by Roumaïssa Gouasmi, Carole Ferraro-Peyret, Stéphane Nancey, Isabelle Coste, Toufic Renno, Cédric Chaveroux, Nicolas Aznar and Stéphane Ansieau
Cancers 2022, 14(11), 2793; https://doi.org/10.3390/cancers14112793 - 04 Jun 2022
Cited by 23 | Viewed by 4829
Abstract
The kynurenine pathway has been highlighted as a gatekeeper of immune-privileged sites through its ability to generate from tryptophan a set of immunosuppressive metabolic intermediates. It additionally constitutes an important source of cellular NAD+ for the organism. Hijacking of its immunosuppressive functions, [...] Read more.
The kynurenine pathway has been highlighted as a gatekeeper of immune-privileged sites through its ability to generate from tryptophan a set of immunosuppressive metabolic intermediates. It additionally constitutes an important source of cellular NAD+ for the organism. Hijacking of its immunosuppressive functions, as recurrently observed in multiple cancers, facilitates immune evasion and promotes tumor development. Based on these observations, researchers have focused on characterizing indoleamine 2,3-dioxygenase (IDO1), the main enzyme catalyzing the first and limiting step of the pathway, and on developing therapies targeting it. Unfortunately, clinical trials studying IDO1 inhibitors have thus far not met expectations, highlighting the need to unravel this complex signaling pathway further. Recent advances demonstrate that these metabolites additionally promote tumor growth, metastatic dissemination and chemoresistance by a combination of paracrine and autocrine effects. Production of NAD+ also contributes to cancer progression by providing cancer cells with enhanced plasticity, invasive properties and chemoresistance. A comprehensive survey of this complexity is challenging but necessary to achieve medical success. Full article
(This article belongs to the Special Issue Targeting Amino Acid Signaling and Metabolism in Cancer)
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