Decoding Epithelial Plasticity: Exploring the Influence of SWI-SNF Complex Mutations on Bladder Cancer Progression

Project summary

Bladder cancer, particularly in its early stages, often carries an excellent prognosis and can be effectively managed with standard treatments. However, in a notable portion of cases (approximately 10-30%), the disease progresses aggressively, invading the bladder's muscle layer and significantly reducing survival rates. Unlike early-stage bladder cancers, these advanced tumours tend to lose their distinct bladder cell identity and revert to a more primitive state. This reversion helps them swiftly adapt to environments outside of the bladder, facilitating tumour growth and spread.

Our initial research suggests a connection between the emergence of these aggressive cancer types and low oxygen levels, which are commonly seen within tumours. This low-oxygen environment activates specific cellular responses to stress. Moreover, certain genetic mutations within bladder cancer cells seem to make them resistant to the damaging effects of low oxygen levels, contributing to their aggressive behaviour. While similar mechanisms have been studied extensively in other cancers, their specific roles in bladder cancer are not well understood.

Our main goal is to understand how these mutations, in combination with low-oxygen environments, can drive the progression of bladder cancer. To achieve this, we will analyze data from bladder cancer samples containing these mutations to identify molecular patterns associated with low oxygen levels and aggressive behaviour. We will also use laboratory models to compare these patterns between cancers with and without genetic mutations in low-oxygen environments. Additionally, we will test drugs targeting both the genetic mutation and the stress response pathways activated by low oxygen to see if they can prevent tumour cells from reverting to their primitive state. The aim is to add these new types of drugs to the portfolio of effective treatments available to patients with bladder cancer. Finally, I aim to validate and pinpoint specific molecular markers of tumour aggressiveness, low oxygen levels, and stress signalling within intact bladder cancer tissue samples. These signatures could be translated into tests that catch life-threatening cancers earlier, in time to cure them.

By gaining a deeper understanding of these processes, I aspire to identify novel targets for treatment, especially for patients afflicted with aggressive bladder cancer subtypes resistant to current therapies. This endeavour holds the promise of improving outcomes and quality of life for individuals grappling with advanced bladder cancer.

Quotes

“I am ecstatic and immensely thankful to be honoured with the Health Informatics and Data Science Award from MOHCCN. This accolade stands as a tribute to the relentless support of my supervisors, mentors, and colleagues. I am eager to utilize my bioinformatics expertise to enhance prognostic tests and identify new therapeutic targets to prevent bladder cancer progression.”

• Andrew John Garven, HI&DS Awardee
  

“This research has the potential to significantly impact bladder cancer treatment and prognosis by uncovering the mechanisms of tumour progression in SWI-SNF complex mutant cancers under hypoxia. Identifying novel prognostic biomarkers and therapeutic targets may lead to enhanced risk assessment tools and personalized treatments, particularly for early-stage non-muscle invasive bladder cancer patients at risk of progression. This work promises to improve our understanding of bladder cancer biology and enhance clinical outcomes.”

• Dr. Amber Simpson, mentor