Metabolic Classification and Intervention Opportunities for Tumor Energy Dysfunction

Monferrer, Ezequiel; Vieco-Martí, I.; López-Carrasco, Amparo; Fariñas, Fernando; Abanades, Sergio; Cruz‐Merino, Luis de la; Noguera, Rosa; Naranjo, Tomás Álvaro

doi:10.3390/metabo11050264

Cited by 8 publications

(4 citation statements)

References 178 publications

(263 reference statements)

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“…Tumours can have different areas with disparate TME features, which could reflect differing genomic aberrations in tumour cells. It is well-known that the centre of the tumour typically has fewer blood vessels and more hypoxia than tumour borders [35], which can influence pH and metabolism, and also induce genomic and epigenomic changes between zones [36]. However, tissue areas of tumours submitted to genetic diagnostics yield little information even without taking ITH into account and this could be among the principal reasons for low reproducibility, not only in diagnostics and treatment but also in bio-medical research [1,37].…”

Section: Discussionmentioning

confidence: 99%

Intra-Tumour Genetic Heterogeneity and Prognosis in High-Risk Neuroblastoma

López-Carrasco

Berbegall

Martín-Vañó

et al. 2021

Cancers

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Spatial ITH is defined by genomic and biological variations within a tumour acquired by tumour cell evolution under diverse microenvironments, and its role in NB patient prognosis is understudied. In this work, we applied pangenomic techniques to detect chromosomal aberrations in at least two different areas of each tumour and/or in simultaneously obtained solid and liquid biopsies, detecting ITH in the genomic profile of almost 40% of HR-NB. ITH was better detected when comparing one or more tumour pieces and liquid biopsy (50%) than between different tumour pieces (21%). Interestingly, we found that patients with ITH analysed by pangenomic techniques had a significantly better survival rate that those with non-heterogeneous tumours, especially in cases without MYCN amplification. Moreover, all patients in the studied cohort with high ITH (defined as 50% or more genomic aberration differences between areas of a tumour or simultaneously obtained samples) survived after 48 months. These results clearly support analysing at least two solid tumour areas (separately or mixed) and liquid samples to provide more accurate genomic diagnosis, prognosis and therapy options in HR-NB.

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Section: Discussionmentioning

confidence: 99%

Intra-Tumour Genetic Heterogeneity and Prognosis in High-Risk Neuroblastoma

López-Carrasco

Berbegall

Martín-Vañó

et al. 2021

Cancers

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“… 21 , 22 Recent studies have showed that some cancer cell lines tend to rely on glycose instead of other nutriments for energy supply. 23 These cells exhibit rapid glucose consumption and lactate secretion. Oncogenic TP53 mutation promotes glucose metabolism in many types of cancer.…”

Section: Discussionmentioning

confidence: 99%

SLC45A4 promotes glycolysis and prevents AMPK/ULK1‐induced autophagy in TP53 mutant pancreatic ductal adenocarcinoma

Chen

Huang

et al. 2021

The Journal of Gene Medicine

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Background: Somatic mutations of the TP53 gene occur frequently in pancreatic ductal adenocarcinoma (PDA). Solute carrier family 45 member A4 (SLC45A4) is a H + -dependent sugar cotransporter. The role of SLC45A4 in PDA, especially in TP53 mutant PDA, remains poorly understood. Methods:We explored the TCGA datasets to identify oncogenes in TP53 mutant PDA., colony formation and 5-ethynyl-2 0 -deoxyuridine (Edu) assays were performed to investigate the function of SLC45A4 in vitro. Glucose consumption, lactate production and ATP production were detected to evaluate glucose utilization.Extracellular acidification rate and oxygen consumption rate assays were used to evaluate glycolysis and oxidative phosphorylation. The subcutaneous xenotransplantation models were conducted to explore the function of SLC45A4 in vivo. RNAsequencing and gene set enrichment analysis were employed to explore the biological alteration caused by SLC45A4 knockdown. Western blotting was performed to evaluate the activation of glycolysis, as well as the AMPK pathway and autophagy.Results: SLC45A4 was overexpressed in PDA for which the expression was significantly higher in TP53 mutant PDA than that in wild-type PDA tissues.Moreover, high level of SLC45A4 expression was tightly associated with poor clinical outcomes in PDA patients. Silencing SLC45A4 inhibited proliferation in TP53 mutant PDA cells. Knockdown of SLC45A4 reduced glucose uptake and ATP production, which led to activation of autophagy via AMPK/ULK1 pathway. Deleting SLC45A4 in TP53 mutant HPAF-II cells inhibited the growth of xenografts in nude mice. Conclusions:The present study found that SLC45A4 prevents autophagy via AMPK/ ULK1 axis in TP53 mutant PDA, which may be a promising biomarker and therapeutic target in TP53 mutant PDA.Wenying Chen and Fengting Huang contributed equally to this work

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“…This review is focused on the regulatory metabolic pathways of both immune and tumor cells, the metabolic differences between stromal and tumor cells and especially the effector and immunosuppressive metabolic pathways of T effectors (T eff ) and memory lymphocytes, M1 and M2 macrophages and myeloid-derived suppressor cells (MDSCs), as well as the role of acidosis and hypoxia in all of these factors. This approach consolidates the hypothesis of cancer as an energy dysfunction [13], where alterations can be found in the metabolic pathways of fatty acids (FAs), amino acids, nucleic acids and carbohydrates that affect immune dysfunction, allowing clinical tumor development. We conclude by discussing the extraordinary plasticity of the immune response, its role in immunotherapy efficacy and measures to modulate energy metabolism that should be implemented in cancer treatment.…”

Section: Introductionmentioning

confidence: 85%

Immunometabolism Modulation in Therapy

et al. 2021

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The study of cancer biology should be based around a comprehensive vision of the entire tumor ecosystem, considering the functional, bioenergetic and metabolic state of tumor cells and those of their microenvironment, and placing particular importance on immune system cells. Enhanced understanding of the molecular bases that give rise to alterations of pathways related to tumor development can open up new therapeutic intervention opportunities, such as metabolic regulation applied to immunotherapy. This review outlines the role of various oncometabolites and immunometabolites, such as TCA intermediates, in shaping pro/anti-inflammatory activity of immune cells such as MDSCs, T lymphocytes, TAMs and DCs in cancer. We also discuss the extraordinary plasticity of the immune response and its implication in immunotherapy efficacy, and highlight different therapeutic intervention possibilities based on controlling the balanced systems of specific metabolites with antagonistic functions.

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Metabolic Classification and Intervention Opportunities for Tumor Energy Dysfunction

Cited by 8 publications

References 178 publications

Intra-Tumour Genetic Heterogeneity and Prognosis in High-Risk Neuroblastoma

Intra-Tumour Genetic Heterogeneity and Prognosis in High-Risk Neuroblastoma

SLC45A4 promotes glycolysis and prevents AMPK/ULK1‐induced autophagy in TP53 mutant pancreatic ductal adenocarcinoma

Immunometabolism Modulation in Therapy

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