Metabolic reprogramming and epithelial‐to‐mesenchymal transition in cancer

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.

[1]  Saugata Hazra,et al.  The basics of epithelial–mesenchymal transition (EMT): A study from a structure, dynamics, and functional perspective , 2019, Journal of cellular physiology.

[2]  Y. Jeng,et al.  Glutaminase 2 stabilizes Dicer to repress Snail and metastasis in hepatocellular carcinoma cells. , 2016, Cancer letters.

[3]  Ying Wang,et al.  Downregulation of FBP1 Promotes Tumor Metastasis and Indicates Poor Prognosis in Gastric Cancer via Regulating Epithelial-Mesenchymal Transition , 2016, PloS one.

[4]  J. Condeelis,et al.  Mechanism of early dissemination and metastasis in Her2+ mammary cancer , 2016, Nature.

[5]  Camille Stephan-Otto Attolini,et al.  Targeting metastasis-initiating cells through the fatty acid receptor CD36 , 2016, Nature.

[6]  H. Ishii,et al.  Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer , 2016, Scientific Reports.

[7]  Yusheng Chen,et al.  SDHB deficiency promotes TGFβ-mediated invasion and metastasis of colorectal cancer through transcriptional repression complex SNAIL1-SMAD3/4 , 2016, Translational oncology.

[8]  C. Frezza,et al.  Oncometabolites: Unconventional triggers of oncogenic signalling cascades , 2016, Free radical biology & medicine.

[9]  Christian Frezza,et al.  Tissue-specific and convergent metabolic transformation of cancer correlates with metastatic potential and patient survival , 2016, Nature Communications.

[10]  K. Muegge,et al.  Chromatin Remodeling Factor LSH Drives Cancer Progression by Suppressing the Activity of Fumarate Hydratase. , 2016, Cancer research.

[11]  Emanuel J. V. Gonçalves,et al.  Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition , 2016, Nature.

[12]  J. Shim,et al.  Targeting Epithelial–Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer , 2016, Molecules.

[13]  R. Weinberg,et al.  Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability , 2016, Science.

[14]  Jianquan Hou,et al.  LDH-A promotes malignant progression via activation of epithelial-to-mesenchymal transition and conferring stemness in muscle-invasive bladder cancer. , 2016, Biochemical and biophysical research communications.

[15]  N. Pavlova,et al.  The Emerging Hallmarks of Cancer Metabolism. , 2016, Cell metabolism.

[16]  Hyun Min Jeon,et al.  Dlx-2 and glutaminase upregulate epithelial-mesenchymal transition and glycolytic switch , 2016, Oncotarget.

[17]  Bjorn Baselet,et al.  Metabolic changes associated with tumor metastasis, part 2: Mitochondria, lipid and amino acid metabolism , 2015, Cellular and Molecular Life Sciences.

[18]  Bjorn Baselet,et al.  Metabolic changes associated with tumor metastasis, part 1: tumor pH, glycolysis and the pentose phosphate pathway , 2015, Cellular and Molecular Life Sciences.

[19]  R. Tauler,et al.  Epithelial-to-mesenchymal transition involves triacylglycerol accumulation in DU145 prostate cancer cells. , 2015, Molecular bioSystems.

[20]  R. Weinberg,et al.  Epithelial-Mesenchymal Plasticity: A Central Regulator of Cancer Progression. , 2015, Trends in cell biology.

[21]  E. Letouzé,et al.  Deciphering the molecular basis of invasiveness in Sdhb-deficient cells , 2015, Oncotarget.

[22]  J. Herranz,et al.  A link between lipid metabolism and epithelial-mesenchymal transition provides a target for colon cancer therapy , 2015, Oncotarget.

[23]  L. Roberts,et al.  Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma , 2015, Scientific Reports.

[24]  Stephen T. C. Wong,et al.  EMT is not required for lung metastasis but contributes to chemoresistance , 2015, Nature.

[25]  X. Wan,et al.  Autocrine motility factor promotes epithelial-mesenchymal transition in endometrial cancer via MAPK signaling pathway. , 2015, International journal of oncology.

[26]  E. Maher,et al.  15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma-paraganglioma syndromes characterized by germline SDHB and SDHD mutations. , 2015, Endocrine-related cancer.

[27]  Eyal Gottlieb,et al.  Oncometabolites: tailoring our genes , 2015, The FEBS journal.

[28]  F. Ji,et al.  Succinate dehydrogenase-deficient gastrointestinal stromal tumors. , 2015, World journal of gastroenterology.

[29]  E. Ruppin,et al.  Fumarate induces redox-dependent senescence by modifying glutathione metabolism , 2015, Nature Communications.

[30]  S. Rorive,et al.  Different levels of Twist1 regulate skin tumor initiation, stemness, and progression. , 2015, Cell stem cell.

[31]  Ting Liu,et al.  Citrate Synthase Expression Affects Tumor Phenotype and Drug Resistance in Human Ovarian Carcinoma , 2014, PloS one.

[32]  J. Nielsen,et al.  Succinate dehydrogenase inhibition leads to epithelial-mesenchymal transition and reprogrammed carbon metabolism , 2014, Cancer & metabolism.

[33]  K. Pienta,et al.  Glycolysis is the primary bioenergetic pathway for cell motility and cytoskeletal remodeling in human prostate and breast cancer cells , 2014, Oncotarget.

[34]  R. Carstens,et al.  Mitochondrial retrograde signaling induces epithelial–mesenchymal transition and generates breast cancer stem cells , 2014, Oncogene.

[35]  J. Settleman,et al.  Metabolic and transcriptional profiling reveals pyruvate dehydrogenase kinase 4 as a mediator of epithelial-mesenchymal transition and drug resistance in tumor cells , 2014, Cancer & metabolism.

[36]  G. Longmore,et al.  Transient SNAIL1 expression is necessary for metastatic competence in breast cancer. , 2014, Cancer research.

[37]  K. Mimori,et al.  Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial–mesenchymal transition , 2014, Proceedings of the National Academy of Sciences.

[38]  C. Cordon-Cardo,et al.  Targeting cancer stem cells to suppress acquired chemotherapy resistance , 2014, Oncogene.

[39]  John M. Asara,et al.  Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function , 2014, Nature.

[40]  T. Copetti,et al.  A mitochondrial switch promotes tumor metastasis. , 2014, Cell reports.

[41]  R. Deberardinis,et al.  Metabolic reprogramming during TGFβ1-induced epithelial-to-mesenchymal transition , 2014, Oncogene.

[42]  R. Weinberg,et al.  Dihydropyrimidine Accumulation Is Required for the Epithelial-Mesenchymal Transition , 2014, Cell.

[43]  M. Simpson,et al.  Germline FH mutations presenting with pheochromocytoma. , 2014, The Journal of clinical endocrinology and metabolism.

[44]  Petra C. Schwalie,et al.  GLUT3 is induced during epithelial-mesenchymal transition and promotes tumor cell proliferation in non-small cell lung cancer , 2014, Cancer & metabolism.

[45]  W. Linehan,et al.  Hereditary leiomyomatosis and renal cell carcinoma , 2014, International journal of nephrology and renovascular disease.

[46]  A. Puisieux,et al.  Oncogenic roles of EMT-inducing transcription factors , 2014, Nature Cell Biology.

[47]  P. Rustin,et al.  Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. , 2014, Human molecular genetics.

[48]  Zhimei Lv,et al.  Lipid accumulation is ahead of epithelial-to-mesenchymal transition and therapeutic intervention by acetyl-CoA carboxylase 2 silence in diabetic nephropathy. , 2014, Metabolism: clinical and experimental.

[49]  Abhishek K. Jha,et al.  Mesenchymal Phenotype Predisposes Lung Cancer Cells to Impaired Proliferation and Redox Stress in Response to Glutaminase Inhibition , 2014, Cancer & Metabolism.

[50]  Samy Lamouille,et al.  Molecular mechanisms of epithelial–mesenchymal transition , 2014, Nature Reviews Molecular Cell Biology.

[51]  Yang Song,et al.  Fructose-Bisphosphate Aldolase A Is a Potential Metastasis-Associated Marker of Lung Squamous Cell Carcinoma and Promotes Lung Cell Tumorigenesis and Migration , 2014, PloS one.

[52]  F. Giancotti.  Mechanisms Governing Metastatic Dormancy and Reactivation , 2013, Cell.

[53]  Wai Leong Tam,et al.  The epigenetics of epithelial-mesenchymal plasticity in cancer , 2013, Nature Medicine.

[54]  J. Massagué,et al.  Origins of metastatic traits. , 2013, Cancer cell.

[55]  Changli Wang,et al.  Succinate Dehydrogenase 5 (SDH5) Regulates Glycogen Synthase Kinase 3β-β-Catenin-mediated Lung Cancer Metastasis* , 2013, The Journal of Biological Chemistry.

[56]  P. Bénit,et al.  SDH mutations establish a hypermethylator phenotype in paraganglioma. , 2013, Cancer cell.

[57]  Kevin W. Eliceiri,et al.  The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis , 2013, Nature Cell Biology.

[58]  Fang Wang,et al.  An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells , 2013, Science.

[59]  Samy Lamouille,et al.  Regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions by microRNAs. , 2013, Current opinion in cell biology.

[60]  Jun Yao,et al.  Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. , 2013, Cancer cell.

[61]  John M. Ashton,et al.  BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. , 2013, Cell stem cell.

[62]  Sridhar Ramaswamy,et al.  Circulating Breast Tumor Cells Exhibit Dynamic Changes in Epithelial and Mesenchymal Composition , 2013, Science.

[63]  W Abou-Kheir,et al.  MiR-1 and miR-200 inhibit EMT via Slug-dependent and tumorigenesis via Slug-independent mechanisms , 2013, Oncogene.

[64]  Jing Yang,et al.  Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. , 2012, Cancer cell.

[65]  Wen-Tsan Chang,et al.  Loss of the respiratory enzyme citrate synthase directly links the Warburg effect to tumor malignancy , 2012, Scientific Reports.

[66]  E. Chen,et al.  Cancer stem cells, tumor dormancy, and metastasis , 2012, Front. Endocrin..

[67]  Joshua M. Korn,et al.  Isocitrate Dehydrogenase (IDH) Mutations Promote a Reversible ZEB1/MicroRNA (miR)-200-dependent Epithelial-Mesenchymal Transition (EMT)* , 2012, The Journal of Biological Chemistry.

[68]  E. Chen.  Mitochondrial dysfunction and cancer metastasis , 2012, Journal of Bioenergetics and Biomembranes.

[69]  Peter H. Sudmant,et al.  Identification of a novel recurrent 1q42.2‐1qter deletion in high risk MYCN single copy 11q deleted neuroblastomas , 2012, International journal of cancer.

[70]  T. Brabletz.  To differentiate or not — routes towards metastasis , 2012, Nature Reviews Cancer.

[71]  X. Jeunemaître,et al.  Epithelial to mesenchymal transition is activated in metastatic pheochromocytomas and paragangliomas caused by SDHB gene mutations. , 2012, The Journal of clinical endocrinology and metabolism.

[72]  Lewis C Cantley,et al.  Inhibition of lung cancer growth: ATP citrate lyase knockdown and statin treatment leads to dual blockade of mitogen‐activated protein Kinase (MAPK) and Phosphatidylinositol‐3‐kinase (PI3K)/AKT pathways , 2012, Journal of cellular physiology.

[73]  Wenjun Guo,et al.  Slug and Sox9 Cooperatively Determine the Mammary Stem Cell State , 2012, Cell.

[74]  E. Salazar,et al.  Linoleic acid induces an EMT-like process in mammary epithelial cells MCF10A. , 2011, The international journal of biochemistry & cell biology.

[75]  A. Feinberg,et al.  Genome-scale epigenetic reprogramming during epithelial to mesenchymal transition , 2011, Nature Structural &Molecular Biology.

[76]  Zhiwei Wang,et al.  Phosphoglucose isomerase/autocrine motility factor mediates epithelial-mesenchymal transition regulated by miR-200 in breast cancer cells. , 2011, Cancer research.

[77]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[78]  K. Struhl,et al.  Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. , 2010, Molecular cell.

[79]  L. Castro-Sánchez,et al.  Arachidonic acid promotes epithelial-to-mesenchymal-like transition in mammary epithelial cells MCF10A. , 2010, European journal of cell biology.

[80]  Julia Schüler,et al.  The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs , 2009, Nature Cell Biology.

[81]  Ken Chen,et al.  Recurring mutations found by sequencing an acute myeloid leukemia genome. , 2009, The New England journal of medicine.

[82]  S. Gygi,et al.  SDH5, a Gene Required for Flavination of Succinate Dehydrogenase, Is Mutated in Paraganglioma , 2009, Science.

[83]  Michael F. Clarke,et al.  Downregulation of miRNA-200c Links Breast Cancer Stem Cells with Normal Stem Cells , 2009, Cell.

[84]  V. Hogan,et al.  Phosphoglucose isomerase/autocrine motility factor mediates epithelial and mesenchymal phenotype conversions in breast cancer. , 2009, Cancer research.

[85]  J. Carney,et al.  The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney–Stratakis syndrome): molecular genetics and clinical implications , 2009, Journal of internal medicine.

[86]  D. Busam,et al.  An Integrated Genomic Analysis of Human Glioblastoma Multiforme , 2008, Science.

[87]  R. Maestro,et al.  Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. , 2008, Cancer cell.

[88]  Wenjun Guo,et al.  The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells , 2008, Cell.

[89]  G. Goodall,et al.  The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1 , 2008, Nature Cell Biology.

[90]  V. Hogan,et al.  Down-regulation of phosphoglucose isomerase/autocrine motility factor results in mesenchymal-to-epithelial transition of human lung fibrosarcoma cells. , 2007, Cancer research.

[91]  S. Ramaswamy,et al.  Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis , 2004, Cell.

[92]  A. Paetau,et al.  Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer , 2002, Nature Genetics.

[93]  Ulrich Müller,et al.  Mutations in SDHC cause autosomal dominant paraganglioma, type 3 , 2000, Nature Genetics.

[94]  B. Devlin,et al.  Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. , 2000, Science.

[95]  Peng Huang,et al.  Glyceraldehyde-3-phosphate dehydrogenase promotes cancer growth and metastasis through upregulation of SNAIL expression. , 2017, International journal of oncology.

[96]  Jun Yao,et al.  Loss of FBP 1 by Snail-Mediated Repression Provides Metabolic Advantages in Basal-Like Breast Cancer , 2017 .

[97]  F. Ducray,et al.  IDH1 and IDH2 mutations in gliomas. , 2009, The New England journal of medicine.

[98]  L. Aaltonen,et al.  Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. , 2004, American journal of human genetics.

[99]  C. Troidl,et al.  SDHC mutations in hereditary paraganglioma/pheochromocytoma , 2004, Familial Cancer.