Environment Impacts the Metabolic Dependencies of Ras-Driven Non-Small Cell Lung Cancer

Abstract

SUMMARY Cultured cells convert glucose to lactate and glutamine is the major source of tricarboxylic acid (TCA) cycle carbon, but whether the same metabolic phenotype is found in tumors is less studied. We infused mice with lung cancers with isotope-labeled glucose or glutamine and compared the fate of these nutrients in tumor and normal tissue. As expected, lung tumors exhibit increased lactate production from glucose. However, glutamine utilization by both lung tumors and normal lung was minimal, with lung tumors showing increased glucose contribution to the TCA cycle relative to normal lung tissue. Deletion of enzymes involved in glucose oxidation demonstrates that glucose carbon contribution to the TCA cycle is required for tumor formation. These data suggest that understanding nutrient utilization by tumors can predict metabolic dependencies of cancers in vivo. Furthermore, these data argue that the in vivo environment is an important determinant of the metabolic phenotype of cancer cells.

Cancer metabolism in space and time: Beyond the Warburg effect

“…lac tate) in highly per fused tu mor ar eas. These above ref er enced stud ies sug gest that the tu mor en vi ron ment is at least as im por tant as the ge net ics of a tu mor for pre dict ing its meta bolic pro file [252][253][254]. An other re cent study also points at the tis sue of ori gin as a ma jor dri ver of the meta bolic be hav ior of a tu mor [268].…”

“…Com par a tively, tu mor de rived cell lines grown in cell cul tures were ad dicted to glu t a mine and highly sen si tive to glu t a m i nase in hibitor CB 839. Im por tantly, the meta bolic phe no type was re verted when can cer cells were in jected back into syn geneic mice, ren der ing can cer cells in sen si tive to glu t a m i nase in hibitors [253]. In an other study [254], in vivo imag ing high lighted the link be tween the tu mor mi croen vi ron ment and the het ero gene ity of tu mor me tab o lism in non small cell lung can cer (NSCLC).…”

“…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.…”

“…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. They showed that tu mor cells mostly rely on glu t a mine con sump tion for pro lif er a tion in vitro, whereas glu t a mine car bon con tri bu tion to the TCA cy cle is min i mal in mouse lung tu mors.…”

“…Can cer cells mostly rely on glu cose and glu t a mine for sur vival and growth in vitro. How ever, strong ev i dence shows that the meta bolic land scape is more com plex in vivo [252][253][254]. It is now clear that can cer me tab o lism is het ero ge neous, with dif fer ent meta bolic phe no types ac cord ing to (i) the cell type, (ii) the cel lu lar lo ca tion and (iii) the bi o log i cal ac tiv ity per formed at a pre cise time.…”