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Abstract PR07: Myc-dependent translation makes an impact: Tailor-made protein expression for cancer development

Our research delineates how the “cancer translatome” can reprogram gene expression at the post-transcriptional level, by controlling the translation of specific subsets of mRNAs during distinct steps of cancer progression. Here, we have genetically engineered a novel mouse model in which two of the...

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Bibliographic Details
Published in:Molecular cancer research 2015-10, Vol.13 (10_Supplement), p.PR07-PR07
Main Authors: Stumpf, Craig, Cunningham, Tom, Ruggero, Davide
Format: Article
Language:English
Online Access:Get full text
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Summary:Our research delineates how the “cancer translatome” can reprogram gene expression at the post-transcriptional level, by controlling the translation of specific subsets of mRNAs during distinct steps of cancer progression. Here, we have genetically engineered a novel mouse model in which two of the most commonly perturbed oncogenes, MYC and KRAS, are stochastically activated in a small number of hepatocytes resulting in a dramatic increase in metastatic tumors, recapitulating the process of liver tumor development in human cancers. Therefore, we have used this model to detail the evolution of gene expression from primary tumor initiation to metastasis at both the transcriptional and translational levels. We used a genome-wide ribosome profiling approach to assess changes in gene expression at the earliest possible time point after oncogenic activation to metastasis formation in order to develop the first functional comprehensive network of widespread changes in translational regulation that occur during the course of tumor development. We characterized networks of translational regulation unique to each individual oncogene, as well as networks that are synergistically regulated upon activation of both oncogenes. For example, we have identified common networks that are translationally induced upon activation of either MYC or KRAS (e.g. protein synthesis, energy metabolism). We discovered that each oncogene also regulates the translation of unique mRNA networks. MYC induces the translation of genes involved in cell proliferation, mRNA splicing, and lipid metabolism, while KRAS specifically induces the translation of stress response genes, especially the pathway that responds to hypoxia. In addition to the additive effects of regulating their cognate mRNA networks, the combination of MYC and KRAS activation in the same cells can also induce a synergistic effect on the translation of new networks including genes involved in integrin signaling, which may partially explain the increased metastasis observed in this mouse model. Additionally, we uncovered independent regulatory mechanisms that may allow for temporal regulation of discrete oncogenic processes, either at the level of transcription or translation, required at different times during the course of tumor development. Understanding the mechanisms and specific targets of translational regulation downstream of MYC and KRAS activation will provide a novel platform from which to develop therapeutic strategie
ISSN:1541-7786
1557-3125
DOI:10.1158/1557-3125.MYC15-PR07