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ERC

MYCNEXT Report Summary

Project ID: 268671
Funded under: FP7-IDEAS-ERC
Country: Italy

Final Report Summary - MYCNEXT (Connecting the activities of c-Myc in genome regulation, cellular growth control and oncogenesis)

The transcription factor Myc, encoded by the c-myc proto-oncogene, binds thousands of loci in the cellular genome, but its involvement in gene-regulatory programs has remained controversial. We addressed this issue with the production of integrated genome-wide profiles for Myc, RNA-PolII binding, histone modifications and gene regulation in various biological systems, including the analysis of (i.) Myc-dependent events during mitogenic activation of mouse fibroblasts and primary B-cells, (ii.) Myc-induced self-renewal in mammary epithelial stem cells, (iii.) ectopic Myc activation in fibroblasts, and (iv.) tumor evolution in vivo in mouse models of Myc-driven lymphoma and liver carcinoma. Thorough assessment of our data together with the available literature, indicate that Myc does not function as a general activator (or "amplifier") of transcriptional activity, but differentially modulates the expression - either up or down - of distinct sets of target genes. Oncogenic activation of Myc causes the deregulation of fundamental cellular processes (e.g. energy metabolism, ribosome biogenesis, cell growth) that foster tumorigenesis and, in some situations, can feed back on global RNA synthesis.

Having mapped Myc-regulated genes in B-cell lymphomas, we carried out secondary genetic screens to determine which of these genes are critical for tumor maintenance. Among others, we unraveled a critical role for genes encoding mitochondrial ribosomal proteins. Inhibition of mitochondrial translation with the antibiotic Tigecycline was synthetic-lethal with Myc activation, impaired respiratory activity and tumor cell survival in vitro, and significantly extended life-span in lymphoma-bearing mice. We have thus identified a novel Myc-induced metabolic dependency that can be targeted by common antibiotics, opening new therapeutic perspectives in Myc-overexpressing tumors.

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