The process by which mRNA is translated into a protein is a highly energetic and meticulous process that is essential for life. However, protein synthesis can also be usurped by cancer to drive cellular transformation, uncontrolled proliferation, evasion of apoptosis, metastasis, and drug resistance (Hsieh et al. Cancer Cell 2010, Hsieh et al. Science Signaling 2015). Work from our laboratory indicates that transcription factors utilize the translation apparatus to shape the cellular proteome (Liu and Horn et al. Science Translational Medicine 2019). Interestingly, this relationship can be co-opted to drive specific cancer behavior at a molecular, cellular, and organismal level in prostate cancer.
1) How does the translation apparatus interface with transcription factors and other regulators of gene expression in the context of genitourinary malignancies?
2) What are the key downstream translational drivers necessary for cancer phenotypes such as lineage plasticity?
3) How can we therapeutically disrupt oncogenic translation?
mRNA specific translation is the mechanism by which distinct mRNAs are preferentially translated to control cellular phenotypes. This can be mediated through the protein synthesis apparatus or changes in mRNA sequence and structure. Our laboratory has been fascinated by the untranslated regions (UTRs) of mRNAs, which are necessary for mRNA metabolism and efficient protein synthesis (Hsieh et al. Nature 2012). Surprisingly, their functionality remains poorly understood particularly in the disease context. Thus, we are deeply investigating how UTR dynamics tune gene expression to impact the multistep process of cancer initiation and progression (Liu and Horn et al. Science Translational Medicine 2019, Schuster and Hsieh Trends in Cancer 2019, Lim et al. Nature Communications 2021).
1) How are UTRs usurped to promote cancer pathogenesis?
2) What are the underlying cis- and trans-regulatory mechanisms that enable oncogenic mRNA specific translation?
Chemical modifications to RNA such as a methylation of adenines and isomerization of uridines have been shown to impact the process of mRNA translation. Work from our laboratory in collaboration with the Bellodi Lab (Lund University) and the Paddison Lab (Fred Hutch) have demonstrated a central role for these types of modifications in shaping the cellular proteome. Importantly, these processes are essential for the maintenance of normal stem cell physiology and the dynamic transitions that occur during erythrocyte differentiation (Guzzi et al. Cell 2018, Kuppers et al. Nature Communications 2019). In addition, through work with the Beronja Lab (Fred Hutch) we are unraveling the critical role of mRNA specific translation in cell fate choice (Cai et al. Cell Stem Cell 2020).
1) How do m6A modifications enable the select translation of mRNA essential for the various stages of erythrocyte differentiation?
2) How is mRNA-specific translation directed in basal epithelial cells of the skin to control self-renewal and differentiation?
In 2015, our laboratory along with Drs. Ming Lam (UW Urology), Jonathan Wright (UW Urology), Bruce Montgomery (UW Oncology), and Funda Vakar-Lopez (UW Pathology) nucleated the first bladder cancer focused rapid autopsy program in the world. We have used this precious resource of late stage tumor specimens to interrogate the genomic underpinning of aggressive bladder cancer and to develop patient derive xenografts and primary cell-based models. Through this work, we have identified distinctions between upper tract urothelial carcinoma and lower tract urothelial carcinoma as well as the potential therapeutic implications of druggable genetic lesions in patients with metastatic bladder cancer (Winters et al. JCI Insight 2019). There are also ongoing projects focused on dissecting translation deregulation in bladder cancer (Jana et al. JCI Insight 2021).
1) To what extent and how does bladder cancer heterogeneity influence disease aggressiveness and response to therapeutics?
2) How is the translation apparatus usurped in urothelial cells to drive the process of transformation?