We have been at the forefront in establishing a new paradigm in cancer biology that imbues a critical function to key oncogenes, such as MYC, towards augmenting ribosome biogenesis and protein synthesis rates as an essential driver of tumorigenesis. Indeed, pioneering pharmacogenetic studies in my lab have established that MYC's oncogenic potential relies on protein synthesis control. Importantly, this suggests a novel avenue for the development of therapies to treat MYC-driven cancers by targeting the addiction of this undruggable oncogene to protein synthesis. However, despite the tremendous untapped potential for novel therapeutics, there is a large gap in our understanding of the cellular and molecular basis for synthetic lethal interactions between oncogenic MYC signaling and enhanced protein synthesis. We have exploited the addiction of MYC- overexpressing cells to elevated protein synthesis rates in order to reveal an entire network of synthetically lethal cellular processes and regulatory nodes that support and mediate MYC-dependent protein synthesis to promote tumorigenesis. Together, we have termed this addiction the MYC protein synthesis-dependent synthetic lethal network. Three critical nodes of this network include (1) an anabolic feed-forward circuit between protein synthesis and nucleotide production that sustains the biosynthetic and bioenergetic demands of MYC tumor cells (2) a novel cis-acting RNA regulatory signature in pro-tumorigenic mRNAs that confers MYC-dependent translational sensitivity, and (3) specialized translational reprogramming of the cancer cell genome. Collectively, these findings lay the foundation for this proposal, which seeks to open a new portal into our understanding of the molecular basis for the addiction of MYC-driven cancers to protein synthesis and identify novel therapeutic approaches that exploit this Achilles' heel of MYC-induced tumorigenesis.
In Aim 1, we will define the mechanisms underlying the anabolic feed-forward circuitry that couples nucleotide metabolism to protein synthesis and assess its therapeutic implications in MYC-induced cancer.
In Aim 2, we will determine the mechanism by which the PRTE, a specialized cis-regulatory element, couples protein and nucleotide biosynthesis in cancer.
In Aim 3, we will define the contribution of global and specific modes of mRNA translation towards the genome-wide translational landscape of oncogenic MYC signaling, employing state-of-the-art ribosome profiling coupled to unique genetic mouse models. Together, these studies will provide unprecedented insight into translational remodeling of the cancer genome by MYC and will define an entire new layer of synthetic lethal interactions, providing the foundation for novel therapies targeting the currently undruggable MYC oncogene.
Overexpression of the Myc protein leads to the development and sustained growth of many of the most aggressive and incurable human tumors. In this proposal, we will identify and characterize the mechanisms by which Myc reprograms one of the cell's fundamental processes, the production of proteins, to drive cancer development. Completion of the aims put forth in this grant will lead to novel biological insights into the underlying mechanisms that cause cancer, as well as the identification of new drug targets and therapeutic approaches that will significantly improve patient outcomes.
| Bu, Yiwen; Yoshida, Akihiro; Chitnis, Nilesh et al. (2018) A PERK-miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival. Nat Cell Biol 20:104-115 |
| Nguyen, Hao G; Conn, Crystal S; Kye, Yae et al. (2018) Development of a stress response therapy targeting aggressive prostate cancer. Sci Transl Med 10: |
| Forester, Craig M; Zhao, Qian; Phillips, Nancy J et al. (2018) Revealing nascent proteomics in signaling pathways and cell differentiation. Proc Natl Acad Sci U S A 115:2353-2358 |
| Truitt, Morgan L; Ruggero, Davide (2016) New frontiers in translational control of the cancer genome. Nat Rev Cancer 16:288-304 |
| Truitt, Morgan L; Conn, Crystal S; Shi, Zhen et al. (2015) Differential Requirements for eIF4E Dose in Normal Development and Cancer. Cell 162:59-71 |
| Pelletier, Jerry; Graff, Jeremy; Ruggero, Davide et al. (2015) Targeting the eIF4F translation initiation complex: a critical nexus for cancer development. Cancer Res 75:250-63 |
| Barna, Maria; Ruggero, Davide (2014) Tailor made protein synthesis for HSCs. Cell Stem Cell 14:423-4 |
| Cunningham, John T; Moreno, Melissa V; Lodi, Alessia et al. (2014) Protein and nucleotide biosynthesis are coupled by a single rate-limiting enzyme, PRPS2, to drive cancer. Cell 157:1088-103 |
| Pourdehnad, Michael; Truitt, Morgan L; Siddiqi, Imran N et al. (2013) Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. Proc Natl Acad Sci U S A 110:11988-93 |
| Gkogkas, Christos G; Khoutorsky, Arkady; Ran, Israeli et al. (2013) Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493:371-7 |
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