The MYC Transcription Factor Network: Elucidating Oncogenic and Tumor Suppressive Pathways

About This Grant

Project Summary/Abstract This application is focused on the MYC network, a group of conserved transcription factors that regulate gene expression programs linked to cell growth and proliferation. The MYC family of transcription factors (TFs) are the “founding” members of the network. While known to be essential for normal development, the expression of MYC family TFs is dysregulated in a wide range of cancers and drives growth-related changes that support tumor initiation, progression, immune escape and chemoresistance. We have shown that critical aspects of MYC’s oncogenic activity occur within the context of the MYC network, which is comprised of related, yet functionally distinct, TFs. We have found that these factors can promote and/or antagonize MYC’s normal and oncogenic activity. The individual network proteins are expressed and regulated in response to different signals (mitogenic, differentiation, growth arrest, metabolic flux) and possess different subcellular localizations and stabilities. Evidence indicates that the network is dynamic and that its effects on cell behavior are affected by changes in the abundance and activity of individual network members. This proposal builds on our findings, using genetically engineered mouse models, that two members of the MYC-network, MAX and MGA, each function as potent tumor suppressors. First, MAX is the obligate dimerization partner of MYC and is required for its transcriptional activity. Surprisingly however, MAX deletion acts to broadly induce neuroendocrine neoplasms in which MYC-MAX genomic binding is abolished, but the MYC proliferative expression signature is reconstituted by multiple shifts in genome occupancy of other network members. Second, deletion of MGA dramatically accelerates tumor progression in a lung adenocarcinoma model. Our goals involve elucidating how perturbation of the MYC network through MAX or MGA loss of function lead to oncogenesis. We hypothesize that significant alterations in enhancer-promoter interactions and chromatin architecture, as well as shifts in protein-protein interactions among network members underlie a more rapid evolution of neoplasia. Moreover, we will determine whether the derepression of meiotic cohesins observed in MGA-deleted tumors contributes to genomic damage and instability. We will also identify functional regions within the large (>3000 residue) MGA protein and screen for specific dependencies and vulnerabilities acquired by both the mutant MAX and MGA cancers. Our work identifies two different ways by which the balance among MYC network TFs can be perturbed. Because MAX and MGA alterations/mutations appear to be pervasive among a wide range of human cancers, the impact of this study lies in its potential to harness our knowledge of the dynamics of this essential gene regulatory network in order to develop novel genetic and chemical avenues to control cancer. Our use of mice in part of this study permits us to recapitulate cancer initiation, progression and metastasis under normal mammalian physiological constraints in an efficient and cost-effective manner.