The Metabolic Profile of Tumors Depends on Both the Responsible Genetic Lesion and Tissue Type

Abstract

SUMMARY The altered metabolism of tumors has been considered a target for anti-cancer therapy. However, the relationship between distinct tumor-initiating lesions and anomalies of tumor metabolism in vivo has not been addressed. We report that MYC-induced mouse liver tumors significantly increase both glucose and glutamine catabolism, whereas MET-induced liver tumors use glucose to produce glutamine. Increased glutamine catabolism in MYC-induced liver tumors is associated with decreased levels of glutamine synthetase (Glul) and the switch from Gls2 to Gls1 glutaminase. In contrast to liver tumors, MYC-induced lung tumors display increased expression of both Glul and Gls1 and accumulate glutamine. We also show that inhibition of Gls1 kills cells that over-express MYC and catabolize glutamine. Our results suggest that the metabolic profiles of tumors are likely to depend on both the genotype and tissue of origin and have implications regarding the design of therapies targeting tumor metabolism.

Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment

“…In support of this view, tumours with the same driving mutations exhibit different metabolic profiles depending on their tissue microenvironment [70].…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…Given the ge netic and meta bolic het ero gene ity of can cers, proper pa tient strat i fi ca tion will be re quired ac cord ing to the meta bolic sta tus of their tu mors in or der to de sign ro bust clin i cal tri als and to ul ti mately tai lor treat ments tar get ing me tab o lism [273,274], even though it is emerg ing that dif fer ent can cers con verge their me tab o lism along side tu mor pro gres sion [198]. Nev er the less, a sys tem atic un der stand ing of how ac ti vated onco genes specif i cally in flu ence me tab o lism, es pe cially in re la tion ship to the tis sue of ori gin [267], will be es sen tial for the suc cess of fu ture clin i cal tri als.…”

“…Al though stud ies on cell cul tures showed that mi to chon dr ial res pi ra tion is lim ited in sev eral can cer cell lines [262][263][264], in vivo data showed that mi to chon dr ial oxy gen con sump tion is not im paired in tu mors and that ox ida tive glu cose me tab o lism is re quired for tu mor growth [265]. The dis crep ancy be tween in vitro and in vivo ob ser va tions pleads for the use of spon ta neously aris ing tu mor mod els, which in te grate dri ver mu ta tions, the tu mor mi croen vi ron ment and the sur round ing 3D tis sue ar chi tec ture [253,266,267]. In a re cent study [253], au thors char ac ter ized glu t a mine me tab o lism in ge net i cally en gi neered mouse mod els of lung can cer.…”

Nature and Nurture: What Determines Tumor Metabolic Phenotypes?

“…These data argue that tumors adapt the normal metabolic program of their tissue-oforigin to support inappropriate cell proliferation. In fact, expressing different oncogenes in the same tissue (MYC and MET in the liver) as well as the same oncogene in different tissues (MYC in liver and lung) had distinct effects on glucose and glutamine metabolism, suggesting that both oncogene and tissue type contribute to the metabolic phenotype of cancers (28).…”