Metabolic reprogramming and cancer progression

In the paper

“Metabolic reprogramming precedes liver cancer in mice with MYC expression in hepatocytes (23).”

What the sources say

• Not checked yetcites [23] Hu S, 13C-pyruvate imaging reveals alterations in glycolysis that precede c-Myc-induced tumor formation and regression. Cell Metab. 14, 131– 142 (2011). doi: 10.1016/j.cmet.2011.04.012 21723511 PMC3858338 source

In the paper

“Mutations in isocitrate dehydrogenase isoform-1 (IDH1) and IDH2 generate the oncometabolite D-2-hydroxyglutarate (D-2HG), which inhibits epigenetic enzymes including histone demethylases and the Ten-eleven translocation (TET) family of 5-methylcytosine hydroxylases.”

What the sources say

• Not checked yetcites [25] Figueroa ME, Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553– 567 (2010). doi: 10.1016/j.ccr.2010.11.015 21130701 PMC4105845 source

In the paper

“The dormancy period between arrival of metastatic cells in a distant organ and appearance of macrometastasis varies widely.”

In the paper

“Despite ubiquitous expression of the metabolic enzyme succinate dehydrogenase (SDH), germline mutations in subunits of this complex cause cancer only in a few sites, including neuroendocrine tissues (paraganglioma), the adrenal gland (pheochromocytoma), and the stomach and small intestine (gastrointestinal stromal tumors) (8–10).”

What the sources say

• Not checked yetcites [8] Baysal BE, Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287, 848– 851 (2000). doi: 10.1126/science.287.5454.848 10657297 source
• Not checked yetcites [9] Benn DE, Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas. Oncogene 22, 1358– 1364 (2003). doi: 10.1038/sj.onc.1206300 12618761 source
• Not checked yetcites [10] Hao HX, SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325, 1139– 1142 (2009). doi: 10.1126/science.1175689 19628817 PMC3881419 source

In the paper

“Second, as the approaches used to assess metabolic phenotypes have become more informative, it has become clear that human tumors are metabolically heterogeneous.”

What the sources say

• Not checked yetcites [2] Kim J, DeBerardinis RJ, Mechanisms and implications of metabolic heterogeneity in cancer. Cell Metab. 30, 434– 446 (2019). doi: 10.1016/j.cmet.2019.08.013 31484055 PMC6730674 source

In the paper

“Therefore, classifying tumors according to the oncogenic driver rather than the tissue of origin may obscure metabolic differences imposed by the original metabolic state of the tissue.”

In the paper

“In the case of the classical tumor suppressor gene TP53, germline mutations result in a somewhat different tissue distribution of cancers than sporadic TP53-mutant cancers in patients who lack germline mutations (7).”

What the sources say

• Not checked yetcites [7] Malkin D, Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233– 1238 (1990). doi: 10.1126/science.1978757 1978757 source

In the paper

“For example, chronic mitochondrial dysfunction in CCPAP may phenocopy loss of von Hippel-Lindau (VHL), the most commonly mutated tumor suppressor in clear cell renal cell carcinoma (ccRCC).”

In the paper

“In mice, oncogenic neuroblastoma Ras viral oncogene homolog (NRas) cooperates with mutations in the epigenetic regulator enhancer of zeste homolog 2 (Ezh2) to produce aggressive leukemias.”

What the sources say

• Not checked yetcites [28] Gu Z, Loss of EZH2 reprograms BCAA metabolism to drive leukemic transformation. Cancer Discov. 9, 1228– 1247 (2019). doi: 10.1158/2159-8290.CD-19-0152 31189531 PMC6726547 source

In the paper

“suggesting an indefinite period of dormancy in immunocompetent hosts (101).”

What the sources say

• Not checked yetcites [101] Armanios MY, Transmission of glioblastoma multiforme following bilateral lung transplantation from an affected donor: Case study and review of the literature. Neuro-oncol. 6, 259– 263 (2004). doi: 10.1215/S1152851703000474 15279719 PMC1871995 source

In the paper

“Metabolite accumulation in the setting of dysfunctional mitochondria can inhibit VHL-dependent degradation of hypoxia-inducible factor-α (HIF-α) subunits, creating a pseudohypoxic state that mimics VHL loss (14).”

What the sources say

• Not checked yetcites [14] Selak MA, Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7, 77– 85 (2005). doi: 10.1016/j.ccr.2004.11.022 15652751 source

In the paper

“Gene expression signatures focused on the metabolic network also bear more similarity to the tissue of origin than to tumors from different organs (4).”

What the sources say

• Not checked yetcites [4] Hu J, Heterogeneity of tumor-induced gene expression changes in the human metabolic network. Nat. Biotechnol. 31, 522– 529 (2013). doi: 10.1038/nbt.2530 23604282 PMC3681899 source

In the paper

“Glioblastoma metastases to the lung were only observed when the lungs of a deceased donor were transplanted into an immunosuppressed patient”

What the sources say

• Not checked yetcites [101] Armanios MY, Transmission of glioblastoma multiforme following bilateral lung transplantation from an affected donor: Case study and review of the literature. Neuro-oncol. 6, 259– 263 (2004). doi: 10.1215/S1152851703000474 15279719 PMC1871995 source

In the paper

“At least in AML, dependence on these mutant enzymes persists after the cancer becomes clinically apparent because mutant IDH inhibitors have therapeutic efficacy in humans (27).”

What the sources say

• Not checked yetcites [27] Stein EM, Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130, 722– 731 (2017). doi: 10.1182/blood-2017-04-779405 28588020 PMC5572791 source

In the paper

“During metastasis, for example, several studies demonstrate that cancer cells need to activate mechanisms to resist oxidative stress, or else these cells are culled by the oxidizing environment of the bloodstream.”

In the paper

“In atypical adenomatous hyperplasias (AAHs) of the lung, premalignant lesions overexpress sodium-dependent glucose transporter 2 (SGLT2).”

What the sources say

• Not checked yetcites [24] Scafoglio CR, Sodium-glucose transporter 2 is a diagnostic and therapeutic target for early-stage lung adenocarcinoma. Sci. Transl. Med. 10, eaat5933 (2018). doi: 10.1126/scitranslmed.aat5933 30429355 PMC6428683 source

In the paper

“Some tumors lack recurrent mutations in canonical tumor suppressors and oncogenes but still harbor stereotyped metabolic properties that distinguish them from nonmalignant tissues.”

What the sources say

• Not checked yetcites [13] Xu J, Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma. eLife 8, e38986 (2019). doi: 10.7554/eLife.38986 30924768 PMC6459676 source

In the paper

“This is consistent with the variable efficacy of therapies aimed at seemingly universal metabolic liabilities in cancer cells, including antifolates and other agents.”

In the paper

“As a result, metabolic features and liabilities are subtype-selective rather than uniform across all cancers (2).”

What the sources say

• Not checked yetcites [2] Kim J, DeBerardinis RJ, Mechanisms and implications of metabolic heterogeneity in cancer. Cell Metab. 30, 434– 446 (2019). doi: 10.1016/j.cmet.2019.08.013 31484055 PMC6730674 source

In the paper

“The tissue of origin and developmental context also determine whether potentially transforming mutations result in cancer initiation (6).”

What the sources say

• Not checked yetcites [6] Levine AJ, Jenkins NA, Copeland NG, The roles of initiating truncal mutations in human cancers: The order of mutations and tumor cell type matters. Cancer Cell 35, 10– 15 (2019). doi: 10.1016/j.ccell.2018.11.009 30645969 PMC6376970 source

In the paper

“Moreover, diets high in saturated fat potentiate the MYC transcriptional program in human and mouse prostate cancer, enhancing cell proliferation (18).”

What the sources say

• Not checked yetcites [18] Labbe DP, High-fat diet fuels prostate cancer progression by rewiring the metabolome and amplifying the MYC program. Nat. Commun. 10, 4358 (2019). doi: 10.1038/s41467-019-12298-z 31554818 PMC6761092 source

In the paper

“Even more fundamentally, it has become increasingly clear that metabolic phenotypes and vulnerabilities evolve as tumors progress from premalignant lesions to locally invasive tumors to metastatic cancer.”

In the paper

“These effects contribute to tumor initiation in acute myelogenous leukemia (AML) by resulting in persistent histone and DNA methylation and impaired cellular differentiation (25).”

What the sources say

• Not checked yetcites [25] Figueroa ME, Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553– 567 (2010). doi: 10.1016/j.ccr.2010.11.015 21130701 PMC4105845 source

In the paper

“Second, although different oncogenes reprogram metabolism in different ways, the tissue in which the oncogene is expressed affects the execution of metabolic reprogramming.”

What the sources say

• Not checked yetcites [5] Yuneva MO, The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab. 15, 157– 170 (2012). doi: 10.1016/j.cmet.2011.12.015 22326218 PMC3282107 source

In the paper

“Similarly, germline mutations in the broadly expressed enzyme fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma, a familial syndrome of uterine and cutaneous leiomyomas and kidney cancer, without susceptibility to more common tumors (11).”

What the sources say

• Not checked yetcites [11] Tomlinson IP, Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat. Genet. 30, 406– 410 (2002). doi: 10.1038/ng849 11865300 source

In the paper

“This suggests that the consequences of TP53 mutation depend on the developmental context.”

In the paper

“This enzyme promotes cancer by allowing cells to generate a large leucine pool, activating the growth-stimulating mechanistic target of rapamycin (mTOR).”

What the sources say

• Not checked yetcites [28] Gu Z, Loss of EZH2 reprograms BCAA metabolism to drive leukemic transformation. Cancer Discov. 9, 1228– 1247 (2019). doi: 10.1158/2159-8290.CD-19-0152 31189531 PMC6726547 source

In the paper

“Other cancers arise from inborn errors of metabolism, in which biallelic germline mutations in metabolic enzymes cause a widespread failure of metabolic homeostasis, but cancer is restricted to a subset of tissues specific for each enzyme (12).”

What the sources say

• Not checked yetcites [12] Erez A, DeBerardinis RJ, Metabolic dysregulation in monogenic disorders and cancer - finding method in madness. Nat. Rev. Cancer 15, 440– 448 (2015). doi: 10.1038/nrc3949 26084394 source

In the paper

“The Warburg effect, a preference for glycolysis and lactate secretion in the presence of oxygen, is an example of a metabolic property under cell-autonomous control by oncogenes in many proliferating cancer cells and tumors (1).”

What the sources say

• Not checked yetcites [1] Vander Heiden MG, Cantley LC, Thompson CB, Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 324, 1029– 1033 (2009). doi: 10.1126/science.1160809 19460998 PMC2849637 source

In the paper

“A study that classified thousands of human tumors found that tissue of origin was a major factor defining DNA methylation and gene expression patterns (3).”

What the sources say

• Not checked yetcites [3] Hoadley KA,, Yau C, Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell 173, 291– 304.e6 (2018). doi: 10.1016/j.cell.2018.03.022 29625048 PMC5957518 source

In the paper

“First, although tumors are readily recognized through gene expression signatures, they retain transcriptomic features of the parental tissue so that tumors arising in the same organ are more similar to each other than tumors arising in different organs.”

What the sources say

• Not checked yetcites [3] Hoadley KA,, Yau C, Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell 173, 291– 304.e6 (2018). doi: 10.1016/j.cell.2018.03.022 29625048 PMC5957518 source

In the paper

“In mice, metabolic reprogramming in response to oncogenic KRas in pancreatic acinar cells promotes acinar-to-ductal metaplasia (ADM), a precursor to pancreatic ductal adenocarcinoma (PDAC) (19).”

What the sources say

• Not checked yetcites [19] Liou GY, Mutant KRas-induced mitochondrial oxidative stress in acinar cells upregulates EGFR signaling to drive formation of pancreatic precancerous lesions. Cell Rep. 14, 2325– 2336 (2016). doi: 10.1016/j.celrep.2016.02.029 26947075 PMC4794374 source

In the paper

“Ezh2 mutations result in enhanced expression of branched-chain amino acid transaminase-1 (Bcat1).”

What the sources say

• Not checked yetcites [28] Gu Z, Loss of EZH2 reprograms BCAA metabolism to drive leukemic transformation. Cancer Discov. 9, 1228– 1247 (2019). doi: 10.1158/2159-8290.CD-19-0152 31189531 PMC6726547 source

In the paper

“PDAC-induced macrophage polarization causes the macrophages to release deoxycytidine, which competitively inhibits the chemotherapeutic agent gemcitabine and lowers its therapeutic efficacy (112).”

What the sources say

• Not checked yetcites [112] Halbrook CJ, Macrophage-released pyrimidines inhibit gemcitabine therapy in pancreatic cancer. Cell Metab. 29, 1390– 1399.e6 (2019). doi: 10.1016/j.cmet.2019.02.001 30827862 PMC6602533 source

In the paper

“Truncal mutations in either of these genes produce a cell-autonomous and persistent addiction to the resulting metabolic alteration (accumulation of D-2HG).”

In the paper

“Metabolic heterogeneity among tumors makes this difficult, even if specific, potent, and well-tolerated inhibitors are available.”

In the paper

“its appearance in diverse preclinical models implies a degree of generalizability”

In the paper

“Ineffective DNA repair in cancer cells that lack FH and SDH renders them sensitive to drugs that block DNA repair.”

In the paper

“In addition to their roles in the TCA cycle, high levels of succinate and fumarate in SDH- and FH-deficient cancers impair homologous recombination DNA repair (109). This repair pathway requires the α-ketoglutarate-dependent histone demethylases KDM4A and KDM4B. Like D-2HG, succinate and fumarate, at high concentrations, inhibit α-ketoglutarate-dependent enzymes, including KDM4A and KDM4B.”

What the sources say

• Not checked yetcites [109] Sulkowski PL, Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. Nat. Genet. 50, 1086– 1092 (2018). doi: 10.1038/s41588-018-0170-4 30013182 PMC6072579 source

In the paper

“Although this model did not assess metastasis, it does suggest a shift in metabolic dependencies during dormancy.”

What the sources say

• Not checked yetcites [103] Viale A, Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628– 632 (2014). doi: 10.1038/nature13611 25119024 PMC4376130 source

In the paper

“These dormant cells display enhanced OXPHOS relative to KRas-expressing cells”

What the sources say

• Not checked yetcites [103] Viale A, Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628– 632 (2014). doi: 10.1038/nature13611 25119024 PMC4376130 source

In the paper

“In some cases, metabolic interactions between cancer cells and the microenvironment promote therapy resistance.”

What the sources say

• Not checked yetcites [111] Apicella M, Increased lactate secretion by cancer cells sustains non-cell-autonomous adaptive resistance to MET and EGFR targeted therapies. Cell Metab. 28, 848– 865.e6 (2018). doi: 10.1016/j.cmet.2018.08.006 30174307 source
• Not checked yetcites [112] Halbrook CJ, Macrophage-released pyrimidines inhibit gemcitabine therapy in pancreatic cancer. Cell Metab. 29, 1390– 1399.e6 (2019). doi: 10.1016/j.cmet.2019.02.001 30827862 PMC6602533 source

In the paper

“When in vivo selection was used to identify latency-competent cancer cells, these tumors exhibited a quiescent-like state reminiscent of stem and progenitor cells (102).”

What the sources say

• Not checked yetcites [102] Malladi S, Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 165, 45– 60 (2016). doi: 10.1016/j.cell.2016.02.025 27015306 PMC4808520 source

In the paper

“As discussed above, mouse PDAC cells subjected to prolonged withdrawal of oncogenic Kras in vivo require OXPHOS to emerge from dormancy (103).”

What the sources say

• Not checked yetcites [103] Viale A, Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628– 632 (2014). doi: 10.1038/nature13611 25119024 PMC4376130 source

In the paper

“and thwarts efforts to target fixed liabilities.”

In the paper

“A recurrent theme in studies on cancer progression is the increased reliance of cancer cells on OXPHOS in advanced stages of disease.”

What the sources say

• Not checked yetcites [103] Viale A, Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628– 632 (2014). doi: 10.1038/nature13611 25119024 PMC4376130 source
• Not checked yetcites [114] Guièze R, Mitochondrial reprogramming underlies resistance to BCL-2 inhibition in lymphoid malignancies. Cancer Cell 36, 369– 384.e13 (2019). doi: 10.1016/j.ccell.2019.08.005 31543463 PMC6801112 source
• Not checked yetcites [115] Farge T, Chemotherapy-resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism. Cancer Discov. 7, 716– 735 (2017). doi: 10.1158/2159-8290.CD-16-0441 28416471 PMC5501738 source

In the paper

“an OXPHOS inhibitor with potent efficacy in mouse models is now in phase 1 clinical trials (116).”

What the sources say

• Not checked yetcites [116] Molina JR, An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat. Med. 24, 1036– 1046 (2018). doi: 10.1038/s41591-018-0052-4 29892070 source

In the paper

“inhibiting OXPHOS reduced tumor recurrence (103).”

What the sources say

• Not checked yetcites [103] Viale A, Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628– 632 (2014). doi: 10.1038/nature13611 25119024 PMC4376130 source

In the paper

“In a mouse pancreatic cancer model, ablating oncogenic Kras from established tumors revealed a fraction of cells that survive and eventually propagate.”

What the sources say

• Not checked yetcites [103] Viale A, Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628– 632 (2014). doi: 10.1038/nature13611 25119024 PMC4376130 source

In the paper

“The most straightforward examples are mutations in metabolic enzymes that permanently alter cellular metabolism and promote the hallmarks of malignancy.”

In the paper

“is responsive to cues that evolve during cancer progression”