Dissecting how mRNA translation drives cancer fate
The process by which mRNA is translated into a protein is a highly regulated and energetically demanding process that is essential for life. However, protein synthesis can be reprogrammed in cancer to drive cellular transformation, lineage plasticity, metastasis, and therapeutic resistance. Work from our laboratory indicates that transcription factors utilize the translation initiation apparatus to shape the cellular proteome in prostate cancer (Liu et al. Science Translational Medicine 2019, Germanos et al. eLIFE 2022). We also discovered that chromatin remodelers play a critical role in regulating translation elongation dynamics to control proteome composition in bladder cancer (Jana et al. Cancer Cell 2023). Together, these fundamental relationships constrain clonal outgrowth or can be co-opted to drive specific cancer behavior at a molecular, cellular, and organismal level. Therapeutically, we have observed that targeting protein synthesis not only impacts the growth and survival of cancer but can post-transcriptionally reprogram its cellular identity to overcome drug resistance (Mishra et al. JCI 2026).
Key questions:
1) Why do distinct transcription factors and chromatin remodelers regulate specific aspects of mRNA translation?
2) How does translational variation influence clonal heterogeneity and lineage state in cancer?
3) What are the non-cell autonomous roles of mRNA translation that impact the fate of cancer?
4) How do small non-coding RNAs promote cancer phenotypes?
Decoding the mechanisms of oncogenic mRNA-specific translation
mRNA-specific translation enables cells to preferentially synthesize proteins from select transcripts, thereby shaping cellular identity and behavior. This selectivity 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 govern multiple aspects of mRNA metabolism, localization, stability, and translation efficiency. Despite their central role in gene regulation, the principles that determine UTR function remain poorly understood particularly in cancer. Thus, we are deeply investigating how UTR dynamics tune gene expression to impact the process of cancer progression. A major focus is understanding how UTR-dependent translation control generates phenotypic heterogeneity, cellular adaptation, and promotes drug resistance. In addition to our mechanistic studies, we have developed unbiased functional-genomic approaches to decode the regulatory language embedded within UTRs and identify cis-regulatory elements that control oncogenic protein synthesis (Lim et al. Nature Communications 2021, Schuster et al. Cell Reports 2023).
Key questions:
1) How are UTRs co-opted to generate cancer cell heterogeneity and phenotypic plasticity?
2) What are the underlying cis- and trans-regulatory mechanisms that enable oncogenic mRNA-specific translation?
3) How do changes in UTR structure impact oncogenic protein synthesis?
4) Can UTR-dependent translational programs be therapeutically targeted?
Defining the biological basis of bladder cancer heterogeneity and evolution
Bladder cancer is characterized by profound heterogeneity that influences tumor initiation, metastasis, and therapeutic response. Since 2015, our laboratory, together with Drs. Ming Lam (UW Urology), Jonathan Wright (UW Urology), Bruce Montgomery (UW Medical Oncology), and Funda Vakar-Lopez (UW Pathology), established a bladder cancer rapid autopsy program. This unique resource has enabled comprehensive molecular profiling of advanced disease and the development of patient-derived xenograft and primary cell models that continue to serve as powerful platforms for biological discovery. Our early studies uncovered fundamental genomic differences between upper tract and lower tract urothelial carcinoma (Winters et al. JCI Insight 2019). Building upon these discoveries, our current research seeks to understand how genetic and translational heterogeneity emerges throughout disease evolution—from normal urothelium and premalignant fields to localized and metastatic bladder cancer. By integrating advanced genomic technologies, functional cancer models, and translational studies, we aim to define the mechanisms that govern tumor evolution, therapeutic resistance, and disease recurrence while identifying new opportunities for precision medicine (Jana et al. JCI Insight 2021).
Key questions:
1) How does somatic mosaicism contribute to bladder cancer initiation?
2) What molecular mechanisms generate cancer heterogeneity and metastatic evolution in bladder cancer?
3) How is mRNA translation reprogrammed during urothelial transformation?
4) Can the mechanisms underlying bladder cancer heterogeneity be therapeutically exploited to improve patient outcomes?