Metabolism and cancer: the future is now

Frezza, Christian

doi:10.1038/s41416-019-0667-3

Cited by 79 publications

(64 citation statements)

References 16 publications

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“…Given our results, we can expand the idea that glycolysis and OXPHOS are present in the same tumor accordingly with subpopulation functionality. So, these results agree that a common feature during cancer progression is metabolic rewiring 44,69 .…”

Section: Discussionsupporting

confidence: 85%

“…To expand this result, Cluster C cells overexpressed mitochondrial genes that are part of the respiratory complexes (MT-ND3, MT-ATP6, MT-CO2, MT-ND4, MT-CYB, MT-CO3, MT-ND2, MT-CO1, MT-ND5, and MT-RNR1) related to mitochondrial oxidative phosphorylation (OXPHOS). Therefore, these observations suggest a metabolic rewiring among this subpopulation, needed to meet energy demands in the cancer cell 43,44 .…”

Section: Insights Of Functional Heterogeneity To Elucidate the Connementioning

confidence: 87%

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Unveiling functional heterogeneity in breast cancer multicellular tumor spheroids through single-cell RNA-seq

Muciño-Olmos

Vázquez-Jiménez

León

et al. 2020

Sci Rep

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Heterogeneity is an intrinsic characteristic of cancer. Even in isogenic tumors, cell populations exhibit differential cellular programs that overall supply malignancy and decrease treatment efficiency. In this study, we investigated the functional relationship among cell subtypes and how this interdependency can promote tumor development in a cancer cell line. To do so, we performed single-cell RNA-seq of MCF7 Multicellular Tumor Spheroids as a tumor model. Analysis of single-cell transcriptomes at twotime points of the spheroid growth, allowed us to dissect their functional relationship. As a result, three major robust cellular clusters, with a non-redundant complementary composition, were found. Meanwhile, one cluster promotes proliferation, others mainly activate mechanisms to invade other tissues and serve as a reservoir population conserved over time. our results provide evidence to see cancer as a systemic unit that has cell populations with task stratification with the ultimate goal of preserving the hallmarks in tumors. Cancer studies have established that tumors are complex and heterogeneous systems. These properties are grounded on genetic variations and diverse microenvironmental conditions that induce sizable differences in gene expression profiles, surface biomarkers, metabolism, growth rates, morphology, metastatic potential and response to therapy at a single cell level 1,2. From a clinical point of view, intratumoral (inside tumors) and intertumoral (between tumors) heterogeneity are critical factors that influence diagnosis outcomes and treatments in patients 1,3. Given their relevance, the understanding of tumor heterogeneity has emerged as a fundamental aim to improve treatment efficiency 4. To portray cancer intratumoral heterogeneity in human tissues, tumor microenvironment and their cellular population have been depicted in genome atlases for different cancer types 5-7. Notwithstanding the relevance of these atlases, big challenges into experimental designs come across to survey heterogeneity in human biopsies. For instance, proper cell dissociation methods must be implemented to reduce the risk of altering the transcriptional landscape 8. Additionally, it is hard to trace tumor dynamics due to invasive procedures and the inherent risk to patients 9. Interestingly, to overcome previous limitations, xenograft and organoid models have been used to emulate the temporal and three-dimensional organization of complex cell populations 10. On the other hand, intratumoral heterogeneity is an intricate property that influences even isogenic models providing complementary prosurvival functional roles, called functional heterogeneity 11,12. Functional heterogeneity is hard to be evaluated in the previously described models because of tumor complex interactions 9. To get the functional heterogeneity basics and design optimal treatments to overcome cancer, in vitro studies are the

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Section: Discussionsupporting

confidence: 85%

Section: Insights Of Functional Heterogeneity To Elucidate the Connementioning

confidence: 87%

Unveiling functional heterogeneity in breast cancer multicellular tumor spheroids through single-cell RNA-seq

Muciño-Olmos

Vázquez-Jiménez

León

et al. 2020

Sci Rep

View full text Add to dashboard Cite

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“…Speci cally, the highest lifetime cumulative risk of incidence of cancers is lung cancer, the most common type of cancer death in 94 countries, in both high and low HDI (Human Development Index) regions [16]. What's worse, despite many years of efforts, the metabolic reprogramming of cancer cells is far beyond fully understanding and there has been no treatment towards this mechanism in clinical practice [17] due to the complicated feature of aberrant metabolism of cancer. Recently, it has been reported that compared with normal tissues, mRNA levels of SFXN1 was much higher in virtually all kinds of human cancers [15].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Sideroflexin1 (SFXN1) Predicts Worse Overall Survival in Lung Adenocarcinoma

Liu¹,

Jiang²,

Wang³

et al. 2020

Preprint

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BackgroundMitochondria are the core organelle of cellular energy and metabolism, also closely related to the growth and survival of cancer cells. This research aimed to discover and evaluate a promising prognostic biomarker, a novel mitochondrial gene—Sideroflexin1 (SFXN1), for lung adenocarcinoma (LUAD).ResultsAnalysis of 594 samples from The Cancer Genome Atlas (TCGA) Lung Cancer Cohort, this present study indicated that SFXN1/2/4/5 were overexpressed in LUAD tissue compared with normal lung tissue whereas only the SFXN1 was associated significantly with the overall survival (OS) from the Kaplan-Meier survival analysis (p=0.00093), suggesting that SFXN1 could be a potential prognostic biomarker. Furthermore, the logistic regression of the correlation of clinicopathological features and the expression status of SFXN1 from 522 patients with LUAD in TCGA revealed that the expression level of SFXN1 was related to Eastern Cooperative Oncology Group (ECOG), clinical stage, tumor size and lymph nodes invasion (all p<0.05). Additionally, overexpression of SFXN1 remained associated positively and independently with a worse prognosis after the multivariate Cox regression (HR=1.486, p=0.022). Functionally, SFXN1 involved in the cell cycle, specifically in DNA replication and meiosis, ATPase activity and folate-dependent one-carbon metabolism from the outcomes of Eastern Cooperative Oncology Group (KEGG) and Gene Ontology (GO) enrichment. ConclusionSFXN1 might promote the proliferation and metabolism of cancer cells and function as a prognostic indicator for LUAD, which may contribute to the development of targeted therapy and the emergence of metabolism-based treatment in clinical practice.

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“…HK2 is one of the rate-limited enzymes in glycolysis pathway, and has been recognized to regulate the malignant phenotypes of cancer cells, including cellular apoptosis and migration capabilities [25, -27]. Aerobic glycolysis is the energy metabolism characteristic of tumor cells and fates the malignant phenotype of tumor cells [28][29][30]. Subcutaneous tumor formation in BALB/c nude mice combined with microPET/CT can effectively explore the tumorigenesis and glucose metabolism level of tumors [31].…”

Section: Introductionmentioning

confidence: 99%

CircCDKN2B-AS1 Interacts with IMP3 to Stabilize Hexokinase 2 mRNA and Facilitate Cervical Squamous Cell Carcinoma Aerobic Glycolysis Progression

Zhang

Zhao

Yang

et al. 2020

Preprint

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Background: Circular RNAs(circRNAs) have been reported to play key roles in the development of various cancers. However, the biological function and clinical significance of most circRNAs are still elusive. The purpose of this study is to explore the function and mechanism of a certain circRNA named circCDKN2B-AS1 in cervical cancer development, and its potential value in clinic. Methods: The qRT-PCR array was conducted to verify the expression level of circCDKN2B-AS1. CCK8 assay, transwell assay, and FCM were undertaken to detect cellular proliferation, migration, and apoptosis, respectively. Seahorse XFe 96 analyzer was used to measure the glycolysis metabolism level. RNA pulldown, RIP, actinomycin-D adding assay and Western Blot were used to screen and elucidate the potential mechanisms. BALB/c nude mice and zebrafish embryo（AB,WT） were used as animal models to investigate tumorigenesis capability.18FDG-microPET/CT was used to detect the glucose metabolism level of subcutaneous tumor in nude mice. Results: CircCDKN2B-AS1, circular isoform of lncRNA CDKN2B-AS1, was upregulated in cervical cancer and precancer tissues. We found that circCDKN2B-AS1 associated with IMP3 protein depending on a specific binding site and regulated the stability of Hexokinase 2(HK2) mRNA, the rate-limiting enzyme of aerobic glycolysis pathway. The expression level of circCDKN2B-AS1 fated the binding of IMP3 to 3’UTR of HK2 mRNA, consequently affects cell malignant phenotypes and aerobic glycolysis of cervical cancer in vitro and in vivo. Mutant circCDKN2B-AS1 lacking of the IMP3 binding site didn’t have such effects. Utilizing an inhibitory peptide to block the interaction between circCDKN2B-AS1 and IMP3 protein impeded the binding of IMP3 to 3’UTR of HK2 mRNA and suppressed aerobic glycolysis in cervical cancer cells.Conclusions: Our findings demonstrate that circCDKN2B-AS1 facilitates aerobic glycolysis by sponging IMP3 protein to stabilize HK2 mRNA, consequently promotes malignant phenotypes in cervical cancer, which may provide a potential approach for cervical cancer therapeutics.

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Metabolism and cancer: the future is now

Abstract: In the last decade, the field of cancer metabolism transformed itself from being a description of the metabolic features of cancer cells to become a key component of cellular transformation. Now, the potential role of this field in cancer biology is ready to be unravelled.

Cited by 79 publications

References 16 publications

Unveiling functional heterogeneity in breast cancer multicellular tumor spheroids through single-cell RNA-seq

Unveiling functional heterogeneity in breast cancer multicellular tumor spheroids through single-cell RNA-seq

Overexpression of Sideroflexin1 (SFXN1) Predicts Worse Overall Survival in Lung Adenocarcinoma

CircCDKN2B-AS1 Interacts with IMP3 to Stabilize Hexokinase 2 mRNA and Facilitate Cervical Squamous Cell Carcinoma Aerobic Glycolysis Progression

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