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Cancers
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Metabolic Rewiring in Cancer
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Metabolic Rewiring in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 15186

Special Issue Editor

Dr. Kim Rosalie Kampen

E-Mail Website
Guest Editor
1. Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. 616, 6200 MD Maastricht, The Netherlands
2. Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium
Interests: metabolism; cancer; radiotherapy; resistance; hypoxia

Special Issue Information

Dear Colleagues,

Metabolic rewiring is an important cancer hallmark. Metabolic rewiring allows cancer cells to become independent and feed their needs for uncontrolled proliferation and survival. Metabolic rewiring comprises an adaptive skill that cancer cells abuse to circumvent therapeutic efficacy and support their microenvironment, with the involvement of oncometabolites. The list of oncometabolites has increased with knowledge over recent years, and now includes fumarate, succinate, L-2-hydroxyglutarate (L-2-HG) and D-2-hydroxyglutarate (D-2-HG). While oncometabolites support pro-oncogenic capabilities of cancer cells, they can also be exploited as novel targets for therapy and biomarkers of disease and therapy responses.In this Special Issue, we will provide a comprehensive overview on metabolic rewiring in cancer. 

Dr. Kim Rosalie Kampen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • metabolism
  • oncometabolites
  • radiotherapy
  • chemotherapy
  • cancer
  • tumor
  • hypoxia
  • technologies
  • biomarkers
  • metabolomics

Published Papers (4 papers)

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Research

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17 pages, 1664 KiB  
Article
NMR-Metabolomics Reveals a Metabolic Shift after Surgical Resection of Non-Small Cell Lung Cancer
by Elien Derveaux, Melvin Geubbelmans, Maarten Criel, Ingel Demedts, Ulrike Himpe, Kurt Tournoy, Piet Vercauter, Erik Johansson, Dirk Valkenborg, Karolien Vanhove, Liesbet Mesotten, Peter Adriaensens and Michiel Thomeer
Cancers 2023, 15(7), 2127; https://doi.org/10.3390/cancers15072127 - 3 Apr 2023
Cited by 3 | Viewed by 2041
Abstract
Background: Lung cancer can be detected by measuring the patient’s plasma metabolomic profile using nuclear magnetic resonance (NMR) spectroscopy. This NMR-based plasma metabolomic profile is patient-specific and represents a snapshot of the patient’s metabolite concentrations. The onset of non-small cell lung cancer (NSCLC) [...] Read more.
Background: Lung cancer can be detected by measuring the patient’s plasma metabolomic profile using nuclear magnetic resonance (NMR) spectroscopy. This NMR-based plasma metabolomic profile is patient-specific and represents a snapshot of the patient’s metabolite concentrations. The onset of non-small cell lung cancer (NSCLC) causes a change in the metabolite profile. However, the level of metabolic changes after complete NSCLC removal is currently unknown. Patients and methods: Fasted pre- and postoperative plasma samples of 74 patients diagnosed with resectable stage I-IIIA NSCLC were analyzed using 1H-NMR spectroscopy. NMR spectra (s = 222) representing two preoperative and one postoperative plasma metabolite profile at three months after surgical resection were obtained for all patients. In total, 228 predictors, i.e., 228 variables representing plasma metabolite concentrations, were extracted from each NMR spectrum. Two types of supervised multivariate discriminant analyses were used to train classifiers presenting a strong differentiation between the pre- and postoperative plasma metabolite profiles. The validation of these trained classification models was obtained by using an independent dataset. Results: A trained multivariate discriminant classification model shows a strong differentiation between the pre- and postoperative NSCLC profiles with a specificity of 96% (95% CI [86–100]) and a sensitivity of 92% (95% CI [81–98]). Validation of this model results in an excellent predictive accuracy of 90% (95% CI [77–97]) and an AUC value of 0.97 (95% CI [0.93–1]). The validation of a second trained model using an additional preoperative control sample dataset confirms the separation of the pre- and postoperative profiles with a predictive accuracy of 93% (95% CI [82–99]) and an AUC value of 0.97 (95% CI [0.93–1]). Metabolite analysis reveals significantly increased lactate, cysteine, asparagine and decreased acetate levels in the postoperative plasma metabolite profile. Conclusions: The results of this paper demonstrate that surgical removal of NSCLC generates a detectable metabolic shift in blood plasma. The observed metabolic shift indicates that the NSCLC metabolite profile is determined by the tumor’s presence rather than donor-specific features. Furthermore, the ability to detect the metabolic difference before and after surgical tumor resection strongly supports the prospect that NMR-generated metabolite profiles via blood samples advance towards early detection of NSCLC recurrence. Full article
(This article belongs to the Special Issue Metabolic Rewiring in Cancer)
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15 pages, 3584 KiB  
Article
Depletion of Fumarate Hydratase, an Essential TCA Cycle Enzyme, Drives Proliferation in a Two-Step Model
by Balakrishnan Solaimuthu, Michal Lichtenstein, Arata Hayashi, Anees Khatib, Inbar Plaschkes, Yuval Nevo, Mayur Tanna, Ophry Pines and Yoav D. Shaul
Cancers 2022, 14(22), 5508; https://doi.org/10.3390/cancers14225508 - 9 Nov 2022
Cited by 2 | Viewed by 1941
Abstract
Fumarate hydratase (FH) is an evolutionary conserved TCA cycle enzyme that reversibly catalyzes the hydration of fumarate to L-malate and has a moonlight function in the DNA damage response (DDR). Interestingly, FH has a contradictory cellular function, as it is pro-survival through its [...] Read more.
Fumarate hydratase (FH) is an evolutionary conserved TCA cycle enzyme that reversibly catalyzes the hydration of fumarate to L-malate and has a moonlight function in the DNA damage response (DDR). Interestingly, FH has a contradictory cellular function, as it is pro-survival through its role in the TCA cycle, yet its loss can drive tumorigenesis. Here, we found that in both non-cancerous (HEK-293T) and cancerous cell lines (HepG2), the cell response to FH loss is separated into two distinct time frames based on cell proliferation and DNA damage repair. During the early stages of FH loss, cell proliferation rate and DNA damage repair are inhibited. However, over time the cells overcome the FH loss and form knockout clones, indistinguishable from WT cells with respect to their proliferation rate. Due to the FH loss effect on DNA damage repair, we assumed that the recovered cells bear adaptive mutations. Therefore, we applied whole-exome sequencing to identify such mutated genes systematically. Indeed, we identified recurring mutations in genes belonging to central oncogenic signaling pathways, such as JAK/STAT3, which we validated in impaired FH-KO clones. Intriguingly, we demonstrate that these adaptive mutations are responsible for FH-KO cell proliferation under TCA cycle malfunction. Full article
(This article belongs to the Special Issue Metabolic Rewiring in Cancer)
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19 pages, 3449 KiB  
Article
MALAT1 as a Regulator of the Androgen-Dependent Choline Kinase A Gene in the Metabolic Rewiring of Prostate Cancer
by Sara De Martino, Egidio Iorio, Chiara Cencioni, Aurora Aiello, Francesco Spallotta, Mattea Chirico, Maria Elena Pisanu, Claudio Grassi, Alfredo Pontecorvi, Carlo Gaetano, Simona Nanni and Antonella Farsetti
Cancers 2022, 14(12), 2902; https://doi.org/10.3390/cancers14122902 - 12 Jun 2022
Cited by 3 | Viewed by 2227
Abstract
Background. Choline kinase alpha (CHKA), an essential gene in phospholipid metabolism, is among the modulated MALAT1-targeted transcripts in advanced and metastatic prostate cancer (PCa). Methods. We analyzed CHKA mRNA by qPCR upon MALAT1 targeting in PCa cells, which is characterized by high dose-responsiveness [...] Read more.
Background. Choline kinase alpha (CHKA), an essential gene in phospholipid metabolism, is among the modulated MALAT1-targeted transcripts in advanced and metastatic prostate cancer (PCa). Methods. We analyzed CHKA mRNA by qPCR upon MALAT1 targeting in PCa cells, which is characterized by high dose-responsiveness to the androgen receptor (AR) and its variants. Metabolome analysis of MALAT1-depleted cells was performed by quantitative High-resolution 1 H-Nuclear Magnetic Resonance (NMR) spectroscopy. In addition, CHKA genomic regions were evaluated by chromatin immunoprecipitation (ChIP) in order to assess MALAT1-dependent histone-tail modifications and AR recruitment. Results. In MALAT1-depleted cells, the decrease of CHKA gene expression was associated with reduced total choline-containing metabolites compared to controls, particularly phosphocholine (PCho). Upon MALAT1 targeting a significant increase in repressive histone modifications was observed at the CHKA intron-2, encompassing relevant AR binding sites. Combining of MALAT1 targeting with androgen treatment prevented MALAT1-dependent CHKA silencing in androgen-responsive (LNCaP) cells, while it did not in hormone-refractory cells (22RV1 cells). Moreover, AR nuclear translocation and its activation were detected by confocal microscopy analysis and ChIP upon MALAT1 targeting or androgen treatment. Conclusions. These findings support the role of MALAT1 as a CHKA activator through putative association with the liganded or unliganded AR, unveiling its targeting as a therapeutic option from a metabolic rewiring perspective. Full article
(This article belongs to the Special Issue Metabolic Rewiring in Cancer)
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Review

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19 pages, 3740 KiB  
Review
Dialysis as a Novel Adjuvant Treatment for Malignant Cancers
by Sture Hobro, Anders Nilsson, Jan Sternby, Carl Öberg, Kristian Pietras, Håkan Axelson, Ana Carneiro, Sara Kinhult, Anders Christensson, Jonas Fors, Steven Maciejewski, Jason Knox, Innas Forsal, Linda Källquist and Viktoria Roos
Cancers 2022, 14(20), 5054; https://doi.org/10.3390/cancers14205054 - 15 Oct 2022
Cited by 1 | Viewed by 8018
Abstract
Cancer metabolism is characterized by an increased utilization of fermentable fuels, such as glucose and glutamine, which support cancer cell survival by increasing resistance to both oxidative stress and the inherent immune system in humans. Dialysis has the power to shift the patient [...] Read more.
Cancer metabolism is characterized by an increased utilization of fermentable fuels, such as glucose and glutamine, which support cancer cell survival by increasing resistance to both oxidative stress and the inherent immune system in humans. Dialysis has the power to shift the patient from a state dependent on glucose and glutamine to a ketogenic condition (KC) combined with low glutamine levels—thereby forcing ATP production through the Krebs cycle. By the force of dialysis, the cancer cells will be deprived of their preferred fermentable fuels, disrupting major metabolic pathways important for the ability of the cancer cells to survive. Dialysis has the potential to reduce glucose levels below physiological levels, concurrently increase blood ketone body levels and reduce glutamine levels, which may further reinforce the impact of the KC. Importantly, ketones also induce epigenetic changes imposed by histone deacetylates (HDAC) activity (Class I and Class IIa) known to play an important role in cancer metabolism. Thus, dialysis could be an impactful and safe adjuvant treatment, sensitizing cancer cells to traditional cancer treatments (TCTs), potentially making these significantly more efficient. Full article
(This article belongs to the Special Issue Metabolic Rewiring in Cancer)
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