Microenvironment mediated alterations to metabolic pathways confer increased chemo-resistance in CD133+ tumor initiating cells

Nomura, Alice; Dauer, Patricia; Gupta, Vineet; McGinn, Olivia; Arora, Nivedita; Majumdar, Kaustav; Uhlrich, Charles; Dalluge, Joseph J.; Dudeja, Vikas; Saluja, Ashok K.; Banerjee, Sulagna

doi:10.18632/oncotarget.10838

Cited by 52 publications

(74 citation statements)

References 43 publications

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“…Accordingly, areas of low perfusion preferentially utilized glucose, while highly perfused regions relied more on other nutrients. These data suggest a role for the tumour microenvironment on the metabolic heterogeneity of lung tumours, as recently reported for mouse models of pancreatic cancer [30][31][32].…”

Section: Cancer Metabolism: the General Picturesupporting

confidence: 84%

Metabolic rewiring in mutant Kras lung cancer

Kerr

Martins

2017

The FEBS Journal

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Lung cancer is the leading cause of cancer-related death worldwide, reflecting an unfortunate combination of very high prevalence and low survival rates, as most cases are diagnosed at advanced stages when treatment efficacy is limited. Lung cancer comprises several disease groups with non small cell lung cancer (NSCLC) accounting for~85% of cases and lung adenocarcinoma being its most frequent histological subtype. Mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) affect~30% of lung adenocarcinomas but unlike other commonly altered proteins (EGFR and ALK, affected in~14% and 7% of cases respectively), mutant KRAS remains untargetable. Therapeutic strategies that rely instead on the inhibition of mutant KRAS functional output or the targeting of mutant KRAS cellular dependencies (i.e. synthetic lethality) are an appealing alternative approach. Recent studies focused on the metabolic properties of mutant KRAS lung tumours have uncovered unique metabolic features that can potentially be exploited therapeutically. We review these findings here with a particular focus on in vivo, physiologic, mutant KRAS activity. Cancer metabolism: the general pictureThe reprogramming of cellular metabolism is now a widely recognized hallmark of cancer [1], involving a complex rearrangement of metabolic and energyproducing networks to support the high proliferation rate of tumour cells and their unique metabolic demands. Arguably, the most striking and wellcharacterized metabolic feature of tumours is their altered glucose metabolism. In the 1920s, Otto Warburg [2] showed that tumour cells exhibit an enhanced avidity for glucose, a critical cell nutrient, compared to normal tissue, and this metabolic phenotype has since been confirmed in a large proportion of tumours. In fact, it is routinely exploited in the clinic to both diagnose and stage tumours through positron emission tomography (PET)-based tumour imaging, which relies on the enhanced uptake of a radioactive fluorine-labelled glucose analogue ( 18 F-fluorodeoxyglucose) by tumour cells relative to normal tissue [3].Warburg also noted that under aerobic conditions, conversion of glucose to lactate (aerobic glycolysis) is significantly more prevalent in tumour cells than in normal ones. Furthermore, he argued that tumour cells rely more on aerobic glycolysis to metabolize glucose than on the more energy-efficient process of mitochondrial oxidative phosphorylation preferentially utilized by normal cells [2]. This glycolytic switch, known as the 'Warburg effect', was initially described as a compensation mechanism for mitochondrial dysfunction in tumours [4], but its causes are now thought Abbreviations GTP, guanosine triphosphate; KO, knockout; KRAS, Kirsten rat sarcoma viral oncogene homologue; LKB1, liver kinase B1; NRF2, Nuclear factor erythroid 2 like 2; NSCLC, non small cell lung cancer; p53, transformation-related protein 53 (Trp53); PC, pyruvate carboxylase; PDAC, pancreatic ductal adenocarcinoma; PDH, pyruvate dehydrogenase; ROS, reactive oxygen species; ...

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Section: Cancer Metabolism: the General Picturesupporting

confidence: 84%

Metabolic rewiring in mutant Kras lung cancer

Kerr

Martins

2017

The FEBS Journal

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“…For ex am ple, in ovar ian can cer, one of the most lethal can cers world wide, cis platin re sis tant cells dis played in creased OX PHOS and ROS lev els com pared to sen si tive cells, and this phe no type was re versed upon phar ma co log i cal in hi bi tion of mi to chon dr ial OX PHOS or ROS scav eng ing [133]. The op po site phe nom e non, chemore sis tance by a low ox ida tive me tab o lism, has been iden ti fied as well [134,135]. De spite that these two types of meta bolic chemore sis tance may ap pear to be op po site, they both act through a de creased ca pa bil ity of mi to chon dria to gen er ate ROS, ei ther by up reg u lat ing an tiox i dant de fenses in a high OX PHOS con text [136] or by de creas ing ROS gen er a tion at the elec tron trans port chain when OX PHOS is low.…”

Section: Metabolic Regulation Of Cancer Cell Deathmentioning

confidence: 94%

Cancer metabolism in space and time: Beyond the Warburg effect

Danhier

Bański

Payen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

177

139

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Available online xxx Keywords:Can cer Me tab o lism Mi to chon dria Het ero gene ity Metas ta sis A B S T R A C T Al tered me tab o lism in can cer cells is piv otal for tu mor growth, most no tably by pro vid ing en ergy, re duc ing equiv a lents and build ing blocks while sev eral metabo lites ex ert a sig nal ing func tion pro mot ing tu mor growth and pro gres sion. A can cer tis sue can not be sim ply re duced to a bulk of pro lif er at ing cells. Tu mors are in deed com plex and dy namic struc tures where sin gle cells can het ero ge neously per form var i ous bi o log i cal ac tiv i ties with dif fer ent meta bolic re quire ments. Be cause tu mors are com posed of dif fer ent types of cells with meta bolic ac tiv i ties af fected by dif fer ent spa tial and tem po ral con texts, it is im por tant to ad dress me tab o lism tak ing into ac count cel lu lar and bi o log i cal het ero gene ity. In this re view, we de scribe this het ero gene ity also in meta bolic fluxes, thus show ing the rel a tive con tri bu tion of dif fer ent meta bolic ac tiv i ties to tu mor pro gres sion ac cord ing to the cel lu lar con text. This ar ti cle is part of a Spe cial Is sue en ti tled Res pi ra tory com plex I, edited by Giuseppe Gas parre, Ro drigue Rossig nol and Pierre Son veaux. Abbreviations: ACL, ATP cit rate lyase; AMPK, adeno sine monophos phate ki nase; ARG1, L argi nine me tab o liz ing en zyme arginase 1; BCAA, branched chain amino acid; Bcl2, B cell lym phoma 2; CAF, can cer as so ci ated fi brob last; CIC, can cer ini ti at ing cell; COX2, cy tochrome ox i dase; CSC, can cer stem cell; CREB, cyclic adeno sine monophos phate re sponse el e ment bind ing pro tein; DEC1, dif fer en tially ex pressed in chon dro cytes 1; EMT, ep ithe lial to mes enchy mal tran si tion; FAK, fo cal ad he sion ki nase; FAS, fatty acid syn thase; FBP, fruc tose 1,6 bis pho s phate; FDG PET, [ F] flu o rodeoxyglu cose positron emis sion to mog ra phy; GAPDH, glyc er alde hyde 3 phos phate de hy dro ge nase; HIF 1, hy poxia ac ti vated fac tor 1; HK2, hex ok i nase 2; HMGB1, high mo bil ity group box 1; HU VEC, hu man um bil i cal vein en dothe lial cell; IFN γ, in ter feron gamma; LDH, lac tate de hy dro ge nase; MEF, murine em bry onic fi brob last; MET, mes enchy mal to ep ithe lial tran si tion; MRI, mag netic res o nance imag ing; mTORC1, mam malian tar get of ra pamycin com plex 1; NSCLC, non small cell lung can cer; OX PHOS, ox ida tive phos pho ry la tion; PDAC, pan cre atic duc tal ade no car ci noma; PHD, pro lyl hy drox y lase; pHe, ex tra cel lu lar pH; pHi, in tra cel lu lar pH; PK, pyru vate ki nase; PPP, pen tose phos phate path way; REDD1, reg u lated in de vel op ment and DNA dam age re sponse 1; RhoA, Ras ho molog gene fam ily, mem ber A; ROS, re ac tive oxy gen species; SASP, senes cence as so ci ated se cre tory phe no type; SCO2, syn the sis of cy tochrome ox i dase 2; SGK 1, serum and glu co cor ti coid reg u lated ki nase 1 Sirt1, sir tuin 1; TAM, tu mor as so ci ated macrophage; TIGAR, TP53 in duced gly col y ...

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“…Studies from our laboratory show that a CD133+ population is associated with the aggressive biology of pancreatic adenocarcinoma 2 . While they are probably not a population that is responsible for the origin of pancreatic tumors, our previously published study definitely show that they are responsible for therapeutic resistance, tumor initiation at very low dilution as well as extreme metastasis 2, 24, 26 . Our studies further show that this population is enriched upon nutritional deprivation, low dose chemotherapy as well as presence of hypoxia 21, 25, 26 .…”

Section: Introductionmentioning

confidence: 68%

Long non-coding RNA GAS5 acts as proliferation “brakes” in CD133+ cells responsible for tumor recurrence

Sharma

Gnamlin

Durden

et al. 2019

Preprint

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Presence of quiescent, therapy evasive population often described as cancer stem cells (CSC) or tumor initiating cells (TIC) is often attributed to extreme metastasis and tumor recurrence.This population is typically enriched in a tumor as a result of microenvironment or chemotherapy induced stress. The TIC population adapts to this stress by turning on cell cycle arrest programs that is a "fail-safe" mechanism to prevent expansion of malignant cells to prevent further injury.Upon removal of the "stress" conditions, these cells restart their cell cycle and regain their proliferative nature thereby resulting in tumor relapse. Growth Arrest Specific 5 (GAS5) is a long-noncoding RNA that plays a vital role in this process. In pancreatic cancer, CD133+ population is a typical representation of the TIC population that is responsible for tumor relapse.In this study, we show for the first time that emergence of CD133+ population coincides with upregulation of GAS5, that reprograms the cell cycle to slow proliferation by inhibiting GR mediated cell cycle control. The CD133+ population further routed metabolites like glucose to shunt pathways like pentose phosphate pathway, that were predominantly biosynthetic in spite of being quiescent in nature but did not use it immediately for nucleic acid synthesis. Upon inhibiting GAS5, these cells were released from their growth arrest and restarted the nucleic acid synthesis and proliferation. Our study thus showed that GAS5 acts as a molecular switch for regulating quiescence and growth arrest in CD133+ population, that is responsible for aggressive biology of pancreatic tumors. 25, 26 . We and others have shown that CD133+ population are generally slow-cycling or quiescent 2, 6, 36 . This indicates that the cell cycle plays an active role in maintenance of this population in a quiescent and slow cycling state.Growth Arrest Specific 5 or GAS5, is a long non-coding RNA regulates cell cycle in a number of mammalian systems including several cancers 7, 15, 16, 23 . It also mediates cell proliferation by regulating CDK6 activity 17 . Studies have also shown that GAS5 forms a positive feedback network with a number of genes involved in self-renewal like Sox2/Oct4, making this long noncoding RNA (LncRNA) a critical player in induction and maintenance of the "stemness" state in a tumor 34 . GAS5 is further involved in regulation of human embryonic stem cell self-renewal by maintaining NODAL signaling 38 . Mechanistically, the effect of GAS5 on cell cycle is regulated by its interaction with the glucocorticoid receptor (GR) 11 . GRs are nuclear receptor proteins that control cell proliferation via their effect on cell cycle 30 . GAS5 interacts with the activated GR

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Microenvironment mediated alterations to metabolic pathways confer increased chemo-resistance in CD133+ tumor initiating cells

Cited by 52 publications

References 43 publications

Metabolic rewiring in mutant Kras lung cancer

Metabolic rewiring in mutant Kras lung cancer

Cancer metabolism in space and time: Beyond the Warburg effect

Long non-coding RNA GAS5 acts as proliferation “brakes” in CD133+ cells responsible for tumor recurrence

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