Several lines of evidence indicate that during transformation epithelial cancer cells can acquire mesenchymal features via a process called epithelial‐to‐mesenchymal transition (EMT). This process ...endows cancer cells with increased invasive and migratory capacity, enabling tumour dissemination and metastasis. EMT is associated with a complex metabolic reprogramming, orchestrated by EMT transcription factors, which support the energy requirements of increased motility and growth in harsh environmental conditions. The discovery that mutations in metabolic genes such as FH, SDH and IDH activate EMT provided further evidence that EMT and metabolism are intertwined. In this review, we discuss the role of EMT in cancer and the underpinning metabolic reprogramming. We also put forward the hypothesis that, by altering chromatin structure and function, metabolic pathways engaged by EMT are necessary for its full activation.
During transformation, epithelial cells undergo a complex phenotypic reprogramming called epithelial‐to‐mesenchymal transition (EMT), whereby they become more motile and invasive. During EMT, cancer cells also profoundly reprogramme their metabolism. In this review, we describe the molecular underpinnings of the metabolic rewiring during EMT and how, in turn, metabolic alterations can trigger EMT.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Cancer cells undergo a multifaceted rewiring of cellular metabolism to support their biosynthetic needs. Although the major determinants of this metabolic transformation have been elucidated, their ...broad biological implications and clinical relevance are unclear. Here we systematically analyse the expression of metabolic genes across 20 different cancer types and investigate their impact on clinical outcome. We find that cancers undergo a tissue-specific metabolic rewiring, which converges towards a common metabolic landscape. Of note, downregulation of mitochondrial genes is associated with the worst clinical outcome across all cancer types and correlates with the expression of epithelial-to-mesenchymal transition gene signature, a feature of invasive and metastatic cancers. Consistently, suppression of mitochondrial genes is identified as a key metabolic signature of metastatic melanoma and renal cancer, and metastatic cell lines. This comprehensive analysis reveals unexpected facets of cancer metabolism, with important implications for cancer patients' stratification, prognosis and therapy.
Mitochondria are intracellular organelles thought to have evolved from an alphaproteobacterium engulfed by the ancestor of the eukaryotic cell, an archeon, two billion years ago. Although ...mitochondria are frequently recognised as the “power plant” of the cell, the function of these organelles go beyond the simple generation of ATP. In fact, mounting evidence suggests that mitochondria are involved in several cellular processes, from regulation of cell death to signal transduction. Given this important role in cell physiology, mitochondrial dysfunction has been frequently associated with human diseases including cancer. Importantly, recent evidence suggests that mitochondrial function is directly regulated by oncogenes and tumour suppressors. However, the consequences of deregulation of mitochondrial function in tumour formation are still unclear. In this review, I propose that mitochondria play a pivotal role in shaping the oncogenic signalling cascade and that mitochondrial dysfunction, in some circumstances, is a required step for cancer transformation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Cancer cells continuously rewire their metabolism to fulfill their need for rapid growth and survival while subject to changes in environmental cues. Thus, a vital component of a cancer cell lies in ...its metabolic adaptability. The constant demand for metabolic alterations requires flexibility, that is, the ability to utilize different metabolic substrates; as well as plasticity, that is, the ability to process metabolic substrates in different ways. In this review, we discuss how dynamic changes in cancer metabolism affect tumor progression and the consequential implications for cancer therapy. SIGNIFICANCE: Recognizing cancer dynamic metabolic adaptability as an entity can lead to targeted therapy that is expected to decrease drug resistance.
Perturbed mitochondrial bioenergetics constitute a core pillar of cancer-associated metabolic dysfunction. While mitochondrial dysfunction in cancer may result from myriad biochemical causes, a ...historically neglected source is that of the mitochondrial genome. Recent large-scale sequencing efforts and clinical studies have highlighted the prevalence of mutations in mitochondrial DNA (mtDNA) in human tumours and their potential roles in cancer progression. In this review we discuss the biology of the mitochondrial genome, sources of mtDNA mutations, and experimental evidence of a role for mtDNA mutations in cancer. We also propose a 'metabolic licensing' model for mtDNA mutation-derived dysfunction in cancer initiation and progression.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Metabolic synthetic lethality in cancer therapy Zecchini, Vincent; Frezza, Christian
Biochimica et biophysica acta. Bioenergetics,
August 2017, 2017-Aug, 2017-08-00, Volume:
1858, Issue:
8
Journal Article
Peer reviewed
Open access
Our understanding of cancer has recently seen a major paradigm shift resulting in it being viewed as a metabolic disorder, and altered cellular metabolism being recognised as a hallmark of cancer. ...This concept was spurred by the findings that the oncogenic mutations driving tumorigenesis induce a reprogramming of cancer cell metabolism that is required for unrestrained growth and proliferation. The recent discovery that mutations in key mitochondrial enzymes play a causal role in tumorigenesis suggested that dysregulation of metabolism could also be a driver of tumorigenesis. These mutations induce profound adaptive metabolic alterations that are a prerequisite for the survival of the mutated cells. Because these metabolic events are specific to cancer cells, they offer an opportunity to develop new therapies that specifically target tumour cells without affecting healthy tissue. Here, we will describe recent developments in metabolism-based cancer therapy, in particular focusing on the concept of metabolic synthetic lethality. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
•Cancer cells undergo specific metabolic changes.•Cancer metabolism can be a target for cancer therapy.•Metabolic liabilities can be identified using synthetic lethality approaches.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
...to a simple accumulation or combination of key “driver” mutations, oncogenesis might be driven by the interplay between the availability of healthy cells harbouring oncogenic mutations along with ...permissive selective pressures. With the advent of the human genome project and technological breakthroughs, cancer genomes are now routinely sequenced, enabling the systematic characterization of somatic genetic alterations observed in thousands of cancers. ...genome-wide CRISPR-Cas9 screens unveiled the importance of the metabolic milieu in determining genetic dependencies and the same cell line in different metabolic contexts displays > 5% significant differential gene dependencies 10. An example of this is genome-scale metabolic models, which provide an integrative framework to tailor metabolic networks to specific tissues or single cells using genomics, transcriptomics and proteomics datasets 14. ...the mathematical representation of the metabolic network enables scalable simulations of the metabolic fluxes and to predict the impact of genetic metabolic perturbations as well as alterations in metabolic environmental conditions.
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Ischemia-reperfusion (IR) injury occurs when blood supply to an organ is disrupted—ischemia—and then restored—reperfusion—leading to a burst of reactive oxygen species (ROS) from mitochondria. It has ...been tacitly assumed that ROS production during IR is a non-specific consequence of oxygen interacting with dysfunctional mitochondria upon reperfusion. Recently, this view has changed, suggesting that ROS production during IR occurs by a defined mechanism. Here we survey the metabolic factors underlying IR injury and propose a unifying mechanism for its causes that makes sense of the huge amount of disparate data in this area and provides testable hypotheses and new directions for therapies.
Ischemia-reperfusion (IR) injury occurs when circulation is disrupted and then restarted. Chouchani et al. propose a unifying framework for an array of data that could explain how ROS is specifically produced during IR, this providing testable hypotheses and new directions for therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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