Signaling to Cancer Cell Growth & Metabolism

Rewiring of the translational machinery by the Myc oncogene.

Our studies of the Myc oncogene have provided a new window into our understanding of how changes in the translation machinery may underlie cellular transformation and tumor initiation. The Myc transcription factor, which is one of the most commonly deregulated oncogenes in human cancers, is a master regulator of ribosome biogenesis, protein synthesis, and cell growth. Strikingly, one of the largest fractions of Myc target genes is directly involved in ribosome biogenesis and/or protein synthesis. However, Myc is also thought to regulate the expression of ~10% of the entire genome. Because Myc simultaneously controls the expression of multiple components of the translation machinery, it has historically been difficult to restore Myc-dependent increases in protein synthesis to normal levels in a cancer setting. One of the most important research advancements that we have made is to genetically thwart Myc-dependent increases in protein synthesis employing a ribosome protein haploinsufficient mouse. This demonstrated for the first time that Myc relies on increases in protein synthesis for cell growth, division and genome instability that is fundamental for cancer initiation and development.

How protein synthesis and metabolism are coupled to drive cancer.

An outstanding and almost completely unexplored question is whether and how cancer cells have evolved the ability to integrate increases in these numerous cellular outputs (e.g. cancer cell metabolome, protein synthesis, biosynthetic components) to achieve a new homeostasis that is typically not present in normal cells. If a cancer cell dials up its protein synthesis output to increase cell growth, how can this be detected and proportionately coordinated with an increase, for example, in cellular metabolites required to fuel enhanced cell proliferation and survival? How might this be achieved?

At present the Myc oncogene is deregulated in greater than 90% of human cancers but is currently undruggable. The identification of these critical nodes, at the nexus of controlling the bioenergetic homeostasis of cancer cells, is of enormous importance as they may represent key vulnerabilities unique to cancer cells and offer new therapeutic targets. A critical research discovery we have made is the demonstration that the production of the two most abundant classes of macromolecules in cancer cells—proteins and nucleic acids—are directly coupled. At the molecular level, this is achieved through translation control of only one key enzyme, phosphoribosyl pyrophosphate synthetase 2 (PRPS2), which is rate limiting for nucleotide production. We discovered that only PRPS2, but not its isoform PRSP1 or the other enzymes involved in nucleotide synthesis, possesses an unusual translational sensor embedded in its 5’UTR that acutely senses increases in protein synthesis and growth stimulation to further coordinate the flow of metabolic intermediates through the entire nucleotide pathway, vital for cancer cell metabolism. Strikingly, we show that PRPS2 is synthetically lethal in Myc overexpressing cancer cells, but the complete deletion of PRPS2 is dispensable for normal organismal development and physiology. Together, these studies identify a translationally anchored anabolic circuit critical for cancer cell survival and expose an unexpected vulnerability for “undruggable” oncogenes, such as Myc.

Our future studies aim to delineate the biochemical basis for PRPS2 translation control via its 5’UTR. We are testing the hypothesis that PRPS2 may represent a key target of convergence downstream all major oncogenic pathways.

Another of our long-term goals is to address whether an overall increase in ribosome biogenesis and protein synthesis, as a consequence of Myc hyperactivation, renders neoplastic cells “super competitors” at the expense of surrounding normal cells. We are seeking to determine how Myc’s ability to regulate protein synthesis and metabolism endows these cells with “super-competitive” potential. We have developed novel genetic tools to induce Myc overexpression in a small number of cells and to simultaneously mark these cells with a fluorescent protein. This will enable us to delineate how Myc overexpressing cells may expand at the expense of surrounding normal tissue and the molecular program that is established at the translation level, which may facilitate this competitive expansion.