Nature and Nurture: What Determines Tumor Metabolic Phenotypes?

Abstract

Understanding the genetic basis of cancer has led to therapies that target driver mutations and has helped match patients with more personalized drugs. Oncogenic mutations influence tumor metabolism, but other tumor characteristics can also contribute to their metabolic phenotypes. Comparison of isogenic lung and pancreas tumor models suggests that use of some metabolic pathways is defined by lineage rather than by driver mutation. Lung tumors catabolize circulating branched chain amino acids (BCAA) to extract nitrogen for nonessential amino acid and nucleotide synthesis, whereas pancreatic cancer obtains amino acids from catabolism of extracellular protein. These differences in amino acid metabolism translate into distinct pathway dependencies, as genetic disruption of the enzymes responsible for utilization of BCAA nitrogen limits the growth of lung tumors, but not pancreatic tumors. These data argue that some cancer metabolic phenotypes are defined by cancer tissue-of-origin and environment and that these features constrain the influence of genetic mutations on metabolism. A better understanding of the factors defining tumor nutrient utilization could be exploited to help improve cancer therapy.

The General Explanation Method with NMR Spectroscopy Enables the Identification of Metabolite Profiles Specific for Normal and Tumor Cell Lines

“…Valine and isoleucine are together with leucine collectively known as the branched‐chain amino acids (BCAAs), whereas NAD is one of the five coenzymes involved in the formation of branched‐chain α‐keto acids (BCKAs). The metabolic concentration profile of the A549 cell line is in accordance with the current understanding of the metabolism of the non‐small lung carcinoma (NSCLC) cells, for which overexpression of branched‐chain aminotransferase 1 (BCAT1) results in increased intracellular concentrations of BCAAs through the amination of BCKAs 17, 18, 19. In support, both glutamic acid and glutathione have active roles in the proliferation processes of the A549 cell line, and an increased concentration of glutathione has also been observed in tumor A549 cells 20, 21.…”

Metabolic orchestration of T lineage differentiation and function

“…The dysregulated growth of cancer cells can directly influence the extracellular environment and multiple studies now strongly suggest that the metabolic phenotype of the tumor governs the ensuing immune response (reviewed in ref. [122,123]). In the context of several solid tumors including hepatocellular carcinomas and stomach/colon tumors, quantitative metabolome profiling has revealed decreased intratumoral concentrations of glucose and glutamine [124,125].…”

Targeted therapy of esophageal squamous cell carcinoma: the NRF2 signaling pathway as target

“…It will be essential to focus on the esophagus to develop therapeutic strategies for NRF2 high ESCC. Additionally, in vivo studies will likely be more reliable than in vitro cell culture studies, as seen in recent cancer metabolism studies …”

“…Additionally, in vivo studies will likely be more reliable than in vitro cell culture studies, as seen in recent cancer metabolism studies. 107,108 Several strategies have been proposed to target the NRF2 signaling pathway for cancer therapy: transcriptional downregulation of NRF2; increased degradation of NRF2 mRNA or decreased translation; enhancement of NRF2 degradation through upregulation/activation of KEAP1-CUL3, ␤-TrCP-SCF, or HRD1; blocking the dimerization of NRF2 with small Maf proteins; and blocking the NRF2-sMaf DNA-binding domain. 109 In addition, NRF2 downstream pathways may also be targeted if they can be shown to be functionally critical for NRF2 high ESCC.…”