Molecular and Metabolic Reprogramming: Pulling the Strings Toward Tumor Metastasis

Hipólito, Ana; Martins, Filipa; Mendes, Cindy; Lopes‐Coelho, Filipa; Serpa, Jacinta

doi:10.3389/fonc.2021.656851

Cited by 12 publications

(12 citation statements)

References 233 publications

(299 reference statements)

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“…It produces lactate while generating less ATP than OXPHOS. Lactate can also be converted to pyruvate by lactate dehydrogenase (LDH), which can then enter the mitochondria to generate ATP through OXPHOS [7,8].…”

Section: Oxphos and Anaerobic Glycolysismentioning

confidence: 99%

“…However, OXPHOS is still important in tumor cell metabolism, with many tumor cells having normal or increased OXPHOS along with accelerated glycolysis [12]. Increased OXPHOS has been linked to more aggressive tumor behavior [8].…”

Section: Mitochondrial Metabolism Adaptationmentioning

confidence: 99%

“…The ETC inhibitor ME344 has been shown to reduce acute myeloid leukemia (AML) cell viability and cell growth with no effect on normal hematopoietic cells [7,15]. In addition, inhibitors of a defective TCA cycle Life 2021, 11, 1351 3 of 56 enzyme, the isocitrate dehydrogenase (AG120/ivosidenib, and AG221/enasidenib), have been FDA-approved for treating IDH-mutated relapsed/refractory AML [7,8,16].…”

Section: Mitochondrial Metabolism As a Therapeutic Targetmentioning

confidence: 99%

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Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

Czegle

Gray

Wang³

et al. 2021

Life

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Hematologic malignancies are known to be associated with numerous cytogenetic and molecular genetic changes. In addition to morphology, immunophenotype, cytochemistry and clinical characteristics, these genetic alterations are typically required to diagnose myeloid, lymphoid, and plasma cell neoplasms. According to the current World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues, numerous genetic changes are highlighted, often defining a distinct subtype of a disease, or providing prognostic information. This review highlights how these molecular changes can alter mitochondrial bioenergetics, cell death pathways, mitochondrial dynamics and potentially be related to mitochondrial genetic changes. A better understanding of these processes emphasizes potential novel therapies.

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Section: Oxphos and Anaerobic Glycolysismentioning

confidence: 99%

Section: Mitochondrial Metabolism Adaptationmentioning

confidence: 99%

Section: Mitochondrial Metabolism As a Therapeutic Targetmentioning

confidence: 99%

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Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

Czegle

Gray

Wang³

et al. 2021

Life

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“…These examples underline that glycolytic and mitochondrial alterations can have anti-or pro-metastatic effects, depending on the tumor type and cellular microenvironment. These strongly emphasize the role of altered metabolism during metastasis [254]. Defining the metabolic profile in various cellular states (during the metastatic cascade) could expand therapeutic targets and precision-based therapy.…”

Section: Tissue Heterogeneity Of Certain Metabolic Enzymes and Their ...mentioning

confidence: 96%

The role of metabolic ecosystem in cancer progression — metabolic plasticity and mTOR hyperactivity in tumor tissues

Sebestyén

Dankó

Sztankovics

et al. 2021

Cancer Metastasis Rev

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Despite advancements in cancer management, tumor relapse and metastasis are associated with poor outcomes in many cancers. Over the past decade, oncogene-driven carcinogenesis, dysregulated cellular signaling networks, dynamic changes in the tissue microenvironment, epithelial-mesenchymal transitions, protein expression within regulatory pathways, and their part in tumor progression are described in several studies. However, the complexity of metabolic enzyme expression is considerably under evaluated. Alterations in cellular metabolism determine the individual phenotype and behavior of cells, which is a well-recognized hallmark of cancer progression, especially in the adaptation mechanisms underlying therapy resistance. In metabolic symbiosis, cells compete, communicate, and even feed each other, supervised by tumor cells. Metabolic reprogramming forms a unique fingerprint for each tumor tissue, depending on the cellular content and genetic, epigenetic, and microenvironmental alterations of the developing cancer. Based on its sensing and effector functions, the mechanistic target of rapamycin (mTOR) kinase is considered the master regulator of metabolic adaptation. Moreover, mTOR kinase hyperactivity is associated with poor prognosis in various tumor types. In situ metabolic phenotyping in recent studies highlights the importance of metabolic plasticity, mTOR hyperactivity, and their role in tumor progression. In this review, we update recent developments in metabolic phenotyping of the cancer ecosystem, metabolic symbiosis, and plasticity which could provide new research directions in tumor biology. In addition, we suggest pathomorphological and analytical studies relating to metabolic alterations, mTOR activity, and their associations which are necessary to improve understanding of tumor heterogeneity and expand the therapeutic management of cancer.

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“…This illustrates an interesting metabolic re-routing in SDH deficiency, which is also seen in tumors in general [ 101 ].…”

Section: Model Systemsmentioning

confidence: 96%

Model systems in SDHx-related pheochromocytoma/paraganglioma

Takács‐Vellai

Farkas

Ősz

et al. 2021

Cancer Metastasis Rev

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Pheochromocytoma (PHEO) and paraganglioma (PGL) (together PPGL) are tumors with poor outcomes that arise from neuroendocrine cells in the adrenal gland, and sympathetic and parasympathetic ganglia outside the adrenal gland, respectively. Many follow germline mutations in genes coding for subunits of succinate dehydrogenase (SDH), a tetrameric enzyme in the tricarboxylic acid (TCA) cycle that both converts succinate to fumarate and participates in electron transport. Germline SDH subunit B (SDHB) mutations have a high metastatic potential. Herein, we review the spectrum of model organisms that have contributed hugely to our understanding of SDH dysfunction. In Saccharomyces cerevisiae (yeast), succinate accumulation inhibits alpha-ketoglutarate-dependent dioxygenase enzymes leading to DNA demethylation. In the worm Caenorhabditis elegans, mutated SDH creates developmental abnormalities, metabolic rewiring, an energy deficit and oxygen hypersensitivity (the latter is also found in Drosophila melanogaster). In the zebrafish Danio rerio, sdhb mutants display a shorter lifespan with defective energy metabolism. Recently, SDHB-deficient pheochromocytoma has been cultivated in xenografts and has generated cell lines, which can be traced back to a heterozygous SDHB-deficient rat. We propose that a combination of such models can be efficiently and effectively used in both pathophysiological studies and drug-screening projects in order to find novel strategies in PPGL treatment.

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Molecular and Metabolic Reprogramming: Pulling the Strings Toward Tumor Metastasis

Cited by 12 publications

References 233 publications

Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

The role of metabolic ecosystem in cancer progression — metabolic plasticity and mTOR hyperactivity in tumor tissues

Model systems in SDHx-related pheochromocytoma/paraganglioma

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