Metabolic reprogramming and cancer progression

In the paper

“Placing mice on a low-carbohydrate, ketogenic diet blunts the hyperglycemia and insulin release that accompany PI3K inhibition, and this improves the efficacy of PI3K inhibitors on tumor growth (113).”

What the sources say

• Supported

  The passage labeled Abstract describing Figure 3A–G reports that a ketogenic diet reduced PI3K inhibitor-induced hyperglycemia and insulin release in mice. The passages describing Figure 4B–C report improved antitumor efficacy when the diet was combined with PI3K inhibitors, and an insulin-rescue experiment supports the proposed mechanism. (LLM, conf=0.94)

  cites [113] Hopkins BD, Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560, 499– 503 (2018). doi: 10.1038/s41586-018-0343-4 30051890 PMC6197057 source

In the paper

“Oncogenic KRas increases the levels of acetyl coenzyme A (CoA) and reactive oxygen species (ROS) before the development of ADM, and inhibiting these phenotypes blocks ADM (19, 20).”

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
• Not checked yetcites [20] Carrer A, Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis. Cancer Discov. 9, 416– 435 (2019). doi: 10.1158/2159-8290.CD-18-0567 30626590 PMC6643997 source

In the paper

“But an alternative tracer, methyl-4-deoxy-4-[18F]-fluoro-α-d-glucopyranoside (Me4FDG), is taken up by SGLT and can identify AAH and low-grade adenocarcinomas of the lung (24).”

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

“A major theme arising from recent research is that pathways that stimulate the growth of localized, treatment-naïve tumors are distinct from and in some cases irrelevant to the activities that drive mortality by supporting metastasis and therapy resistance.”

In the paper

“Many epidemiological studies report associations between obesity and cancer, and a large prospective analysis of more than 900,000 Americans found greater than a 50% increase in cancer mortality in patients with the highest body mass index (15, 16).”

What the sources say

• Not checked yetcites [15] Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ, Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 348, 1625– 1638 (2003). doi: 10.1056/NEJMoa021423 12711737 source
• Not checked yetcites [16] Lauby-Secretan B, Body fatness and cancer-Viewpoint of the IARC Working Group. N. Engl. J. Med. 375, 794– 798 (2016). doi: 10.1056/NEJMsr1606602 27557308 PMC6754861 source

In the paper

“SGLT2 does not transport the common cancer imaging tracer 18fluoro-2-deoxyglucose (FDG), and thus, these lesions are poor candidates for FDG-PET (positron emission tomography) imaging.”

In the paper

“Microenvironmental and genetic factors appear to induce selective pressures that drive clonal evolution within tumors, and this can create or eliminate metabolic liabilities while facilitating cancer progression.”

In the paper

“These studies demonstrate the functional and therapeutic relevance of metabolic reprogramming early in tumorigenesis.”

In the paper

“Silencing Bcat1 reduces leukemia initiation, and overexpressing this enzyme promotes NRas-driven leukemia initiation even in cells that lack Ezh2 mutations (28).”

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 studies in humans and mice report metabolic changes in premalignant colonic polyps, some of which are retained in adenocarcinomas (21, 22).”

What the sources say

• Not checked yetcites [21] Backshall A, Detection of metabolic alterations in non-tumor gastrointestinal tissue of the Apc(Min/+) mouse by (1) H MAS NMR spectroscopy. J. Proteome Res. 8, 1423– 1430 (2009). doi: 10.1021/pr800793w 19159281 source
• Not checked yetcites [22] Phillips CM, Upregulation of cystathionine-β-synthase in colonic epithelia reprograms metabolism and promotes carcinogenesis. Cancer Res. 77, 5741– 5754 (2017). doi: 10.1158/0008-5472.CAN-16-3480 28923859 PMC5668191 source

In the paper

“In early-stage, premalignant liver, MYC drives enhanced conversion of pyruvate to alanine, whereas later-stage malignant lesions convert pyruvate to lactate.”

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

“Diabetes increases the frequency of KRAS variants in human pancreas, possibly through the effects of chronic hyperglycemia on nucleotide balance (17).”

What the sources say

• Not checked yetcites [17] Hu CM, High glucose triggers nucleotide imbalance through O-GlcNacylation of key enzymes and induces KRAS mutation in pancreatic cells. Cell Metab. 29, 1334– 1349.e10 (2019). doi: 10.1016/j.cmet.2019.02.005 30853214 source

In the paper

“The emerging view of cancer metabolism is that it is flexible and context-specific, with few fixed, broadly applicable liabilities.”

In the paper

“Transgenic MYC induces metabolic changes in both liver tumors and lung tumors but activates glutamine catabolism in lung tumors and glutamine synthesis in liver tumors.”

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

“Nevertheless, a detailed molecular analysis revealed a low genomic burden of point mutations and copy-number variants, no recurrent nonsynonymous mutations, and a DNA methylation pattern that resembles the nonmalignant kidney.”

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

“These tumors bear metabolomic signatures that suggest oxidative stress, suppressed oxidative metabolism, and depletion of mitochondrial DNA and RNA.”

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

“Recently described OXPHOS inhibitors display enhanced toxicity against cultured cancer cells compared with either nontransformed cells or other cancer cells with metabolic properties that allow them to compensate for OXPHOS impairment (116, 117). It is encouraging that these agents also suppress growth of susceptible tumors in mice, using doses that are well-tolerated over the short term.”

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
• Not checked yetcites [117] Shi Y, Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma. Nature 567, 341– 346 (2019). doi: 10.1038/s41586-019-0993-x 30842654 PMC6655586 source

In the paper

“In human prostate cancer, tumor grade correlates with MCT1 expression and with imaging of 13C-lactate after injection of hyperpolarized 13C-pyruvate (122).”

What the sources say

• Not checked yetcites [122] Granlund KL, Hyperpolarized MRI of human prostate cancer reveals increased lactate with tumor grade driven by monocarboxylate transporter 1. Cell Metab. 31, 105– 114.e3 (2020). doi: 10.1016/j.cmet.2019.08.024 31564440 PMC6949382 source

In the paper

“PI3K inhibitors suppress glucose uptake by the muscle and other tissues, resulting in elevated blood glucose and pancreatic insulin release after administration of the drug. The insulin surge reactivates PI3K signaling in the tumor, limiting the efficacy of PI3K inhibitors on tumor growth.”

What the sources say

• Not checked yetcites [113] Hopkins BD, Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560, 499– 503 (2018). doi: 10.1038/s41586-018-0343-4 30051890 PMC6197057 source

In the paper

“Evidence also indicates that metabolic phenotypes evolve as cancer progresses, with new dependencies emerging in the context of therapy resistance and metastasis.”

In the paper

“Glutamine addiction is a common feature of cultured cancer cells, and early attempts to target this pathway in vivo used the glutamine analog 6-diazo-5-oxo-l-norleucine (DON). By inhibiting a myriad of enzymes that use glutamine as a substrate, DON kills cancer cells but is unacceptably toxic to the gastrointestinal tract and other tissues, limiting its clinical development.”

In the paper

“The insights reviewed above indicate that cancer cell metabolism is flexible and heterogeneous”

In the paper

“OXPHOS also promotes resistance to the antimetabolite cytarabine in mouse models of AML (115). Cells persisting after cytarabine treatment and preexisting cells with innate cytarabine resistance both displayed enhanced OXPHOS. Cytarabine treatment in AML-bearing mice spares cells with high levels of OXPHOS, and cytarabine-resistant cells are susceptible to OXPHOS inhibitors (115).”

What the sources say

• 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

“A new probe, 4-[18F]fluorobenzyl-triphenylphosphonium (18F-BnTP), accumulates in tumors in proportion to their reliance on OXPHOS (123). In mouse models of lung cancer, 18F-BnTP imaging predicts sensitivity to OXPHOS inhibition, regardless of whether or not the tumors take up 18FDG.”

What the sources say

• Not checked yetcites [123] Momcilovic M, In vivo imaging of mitochondrial membrane potential in non-small-cell lung cancer. Nature 575, 380– 384 (2019). doi: 10.1038/s41586-019-1715-0 31666695 PMC7328016 source

In the paper

“First, 2-HG accumulation in IDH1- and IDH2-mutant tumors is a rare example in which the metabolite directly reports the oncogenic driver and potential therapy (Fig. 4). Proton magnetic resonance spectroscopy can noninvasively track 2-HG abundance in IDH-mutant gliomas, predicting both disease progression and response to therapy through longitudinal 2-HG measurements (120).”

What the sources say

• Not checked yetcites [120] Choi C, Prospective longitudinal analysis of 2-hydroxyglutarate magnetic resonance spectroscopy identifies broad clinical utility for the management of patients with IDH-mutant glioma. J. Clin. Oncol. 34, 4030– 4039 (2016). doi: 10.1200/JCO.2016.67.1222 28248126 PMC5477829 source

In the paper

“Lactate export by the cancer cells induces neighboring fibroblasts to secrete hepatocyte growth factor, which activates its receptor tyrosine kinase c-MET on cancer cells. Consequently, the cancer cells sustain oncogenic signaling even in the presence of EGFR inhibitors (111).”

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

In the paper

“Clinical efficacy of mutant IDH1 and −2 inhibitors has been demonstrated in AML patients, with clinical trials in solid tumors now under way.”

In the paper

“In chronic lymphocytic leukemia, acquired resistance to venetoclax–an inhibitor of the antiapoptotic protein B cell lymphoma-2 (BCL-2)–involves increased mitochondrial mass and enhanced OXPHOS (114). Inhibiting OXPHOS increases venetoclax sensitivity in culture and in vivo.”

What the sources say

• 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

In the paper

“Recent work in cancer metabolism has focused on assessing metabolic phenotypes in native microenvironments in humans and mice. This has produced a greater appreciation for metabolic heterogeneity among tumors, expanding the scope of metabolic dependencies beyond the classical pathways that dominate metabolism in culture.”

In the paper

“However, most metabolic therapies lack biomarkers, and conventional molecular analyses such as DNA and RNA sequencing usually prove to be inadequate surrogates for metabolism.”

In the paper

“Once dormant cells begin to proliferate, anabolic pathways involving biomass assimilation are presumably activated to support progression to macrometastasis (Fig. 3).”

In the paper

“In addition to its epigenetic effects, D-2HG inhibits enzymes from the canonical metabolic network (104). Such enzymes include transaminases that produce glutamate for glutathione biosynthesis, rendering IDH-mutant gliomas susceptible to treatments that deplete glutamate and enhance oxidative stress (105).”

What the sources say

• Not checked yetcites [104] Lu C, IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474– 478 (2012). doi: 10.1038/nature10860 22343901 PMC3478770 source
• Not checked yetcites [105] McBrayer SK, Transaminase inhibition by 2-hydroxyglutarate impairs glutamate biosynthesis and redox homeostasis in glioma. Cell 175, 101– 116.e25 (2018). doi: 10.1016/j.cell.2018.08.038 30220459 PMC6219629 source

In the paper

“FH and SDH mutations also create truncal metabolic aberrations. These mutations induce permanent restructuring of the TCA cycle and result in numerous metabolic liabilities in preclinical models (106–108).”

What the sources say

• Not checked yetcites [106] Frezza C, Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature 477, 225– 228 (2011). doi: 10.1038/nature10363 21849978 source
• Not checked yetcites [107] Lussey-Lepoutre C, Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism. Nat. Commun. 6, 8784 (2015). doi: 10.1038/ncomms9784 26522426 PMC4632646 source
• Not checked yetcites [108] Adam J, A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia. Cell Rep. 3, 1440– 1448 (2013). doi: 10.1016/j.celrep.2013.04.006 23643539 PMC3675675 source

In the paper

“Intravenous infusion of 13C-lactate into human non-small-cell lung cancer patients and mice bearing patient-derived melanomas identified tumors with a propensity for future metastasis, which required MCT1-dependent lactate transport in the mice (58, 100).”

What the sources say

• Not checked yetcites [58] Faubert B, Lactate metabolism in human lung tumors. Cell 171, 358– 371.e9 (2017). doi: 10.1016/j.cell.2017.09.019 28985563 PMC5684706 source
• Not checked yetcites [100] Tasdogan A, Metabolic heterogeneity confers differences in melanoma metastatic potential. Nature 577, 115– 120 (2020). doi: 10.1038/s41586-019-1847-2 31853067 PMC6930341 source