Nuclear forms of AXL and TYRO3 receptors in bladder cancer

Faculty Development Competitive Research Grants Program 2025-2027

Muscle-Invasive Bladder Cancer (MIBC) is not only one of the most expensive cancers to treat, but also the recommended international guidelines for managing MIBC have remained largely unchanged for decades. Therefore, developing novel treatment schemes for MIBC is considered an unmet need in oncology.
Our preliminary results and literature data indicate that two members of the TAM family of receptor tyrosine kinases (RTKs), AXL and TYRO3, can serve as potential targets and predictive biomarkers in MIBC. In addition to their canonical functions as membranous receptors, the non-canonical role of RTKs in other cellular compartments, including nuclei, has been described. RTKs can be imported to nuclei as full-length proteins via the endocytic pathway or as truncated C-terminal cytoplasmic domains as a result of RIP (Regulated Intramembrane Proteolysis). Importantly, nuclear trafficking of RTKs is increasingly recognised as a process promoting tumour progression and resistance to therapies.
The current proposal investigates the nuclear trafficking of AXL and TYRO3 in bladder cancer cells. It is driven by a hypothesis that transcriptional (promoter usage) and post-transcriptional (alternative splicing) regulation generates different protein isoforms with different sensitivities to RIP and nuclear targeting abilities. We plan to test this hypothesis and investigate the biological functions of nuclear forms of TYRO3 and AXL.
Research on non-canonical AXL—and TYRO3-regulated pathways is poised to contribute to developing personalised therapy in the future and, therefore, meets societal needs in Kazakhstan. As TAM signalling is commonly implicated in breast, ovarian, and lung cancers and malignant melanoma, the knowledge gained in our study will be readily applied to these tumour types.