Dysregulation of protein synthesis is commonly seen in cancer, yet it is unclear how this dysregulation affects stem cell behaviors that can promote aberrant growth. In normal development, protein synthesis is tightly controlled to maintain balanced cell fate decisions and proper tissue growth. However, during oncogenesis, translation is reprogrammed to support a wide range of cancer cell behaviors, such as rapid proliferation and increased survival. While previous studies have described oncogene-induced translational changes, there has been limited functional analysis of how these translational differences alter stem cell fate choice to disrupt tissue homeostasis. This project aims to address this gap in our fundamental understanding of oncogenic growth. We will characterize translationally-regulated cell fate choices by manipulating the translational machinery in the epidermis, a tissue ideally suited for studying stem cell fate. We have identified translation initiation factor Eif2b5 as a positive growth regulator in an oncogenic HrasG12V model. Preliminary studies in embryonic murine epidermis reveal that Eif2b5 elevates translation rate and drives tissue growth in an oncogene- specific manner. Intriguingly, Eif2b5 also promotes both HrasG12V progenitor cell proliferation and differentiation, which have opposing effects on overall tissue growth. We now seek to understand how this oncogene-induced translational reprogramming disrupts normal cell fate balance to drive tumor formation. We will first expand our preliminary studies to mechanistically dissect how HrasG12V signaling induces translational upregulation. Then, we will investigate how HrasG12V dysregulates EIF2B5-dependent translation of cell fate regulators to promote oncogenic growth. We have already profiled the HrasG12V translatome and identified the subset of oncogenic genes that are translationally regulated by EIF2B5. From this gene set, we will characterize top candidate cell fate regulators to segregate the translational mechanisms governing proliferation and differentiation and establish their roles in oncogenic growth. Collectively, these studies will provide a comprehensive understanding of the oncogene-induced translational landscape and how it can be therapeutically targeted.
Dysregulated translation of the cancer genome is a common feature of most human cancers. Understanding how this process alters stem cell behavior holds great promise to transform current therapeutic strategies. This study utilizes murine epidermis to examine translationally-regulated stem cell fate decisions and underlying signaling pathways that drive oncogenesis.
