top of page
Pearson Lab Overcoming the complexity of cancer
Cancer is a complex disease, and this complexity hinders successful diagnosis and treatment. A critical aspect of improving patient outcome is to find ways to overcome this complexity. One approach to address this is to identify overarching principles of cancer biology that span tumor type, which will allow us to develop broadly relevant therapies. For example, we found that cancers can be simplified into just two types (termed "YAP-on" or "YAP-off") based on distinct activities of a single transcriptional complex. Our goal is to understand the molecular basis of these fundamental "rules" of cancer and how we can exploit these to pinpoint better cancer treatments.
Understanding the molecular basis of binary cancer classes
We demonstrated that all cancers can be functionally stratified into binary YAP-on and YAP-off classes, which importantly exhibit unique therapeutic and genetic vulnerabilities. In YAP-on cancers, the transcriptional co-activators, YAP and TAZ, drive oncogenesis via TEAD transcription factors. In contrast, we identified a broad group of YAP-off cancers where YAP/TAZ-TEAD are instead tumor suppressors. Mechanistically, we found that YAP/TAZ-TEAD engage distinct enhancers to regulate unique transcriptional targets in YAP-on and YAP-off cancers, which underlies the opposite pro- vs. anti-cancer activities in each class. We will now employ genomic, proteomic and pharmacological approaches to:
Explore how YAP/TAZ-TEAD are recruited to distinct genes in YAP-on vs. YAP-off cancers.
Understand how this contributes to controlling YAP-off epigenetic state.
Test whether this unique axis can be therapeutically targeted to better treat YAP-off cancers.
Exploiting the YAP-off state to better treat aggressive cancers
YAP-off cancers consist of many neural and neuroendocrine cancers. Of particular clinical relevance are small cell neuroendocrine cancers, such as small cell lung cancer and drug-resistant neuroendocrine prostate cancer, which are among some of the most aggressive cancers that exist. Outcomes for these cancers are dismal, and therapeutic options are extremely limited. We found that YAP-on and YAP-off cancers exhibit unique therapeutic vulnerabilities, highlighting novel treatment strategies for YAP-off cancers. Using functional genomic and pharmacological approaches we will:
Work to unravel the molecular basis for these unique vulnerabilities of YAP-on vs. YAP-off cancers.
Explore the utility of YAP-off selective drugs for the treatment of highly aggressive neural and neuroendocrine cancers.
Employ a "synthetic lethality" screening approach to further improve the efficacy of these therapies towards YAP-off cancers.
Understanding the molecular basis of therapy-driven class-switching
Lineage plasticity allows cancers to jump from a YAP-on to a YAP-off state as a mechanism of drug resistance. However, what drives these lineage conversions is unknown. We will apply single cell and functional genomic approaches to human and mouse models to identify key drivers of these conversions. We will also work with clinician scientists at CancerCare Manitoba to validate these findings in human patients and will work to establish new PDX models to better understand the mechanisms that drive YAP-on to YAP-off class-switching. Together, this allow us to develop strategies to block these lethal transitions.
bottom of page