ß-catenin Roles and Dynamics in Wilms Tumors

Cancer remains one of the leading causes of death and morbidity in children. Despite great advances in treatment strategies, anti-cancer therapies in childhood often have lifelong effects. Some tumors, which typically appear in early childhood, arise from the abnormal expression of an oncogene in developing organs and then manifest shortly after birth. An oncogene is a gene which in certain circumstances can transform a cell into a tumor cell. The same gene often plays an important role in organ development with a fine-tuned expression in space and time. Nephroblastoma, which is also called Wilms tumor (WT), is the most common childhood kidney cancer. The genetic landscape of WT is very diverse and how these mutations contribute to WT is not fully understood. The protein beta- catenin is believed to be one of the drivers of WT. beta-catenin plays a role in the regulation of normal kidney development but also in WT initiation and cancer progression. These diverse functions are attributed to beta-catenins ability to modulate gene expression: Depending on context, it participates in the regulation of genes associated with cell proliferation, survival, differentiation, and stem cell maintenance, among others. Intriguingly, I have previously observed various expression patterns of beta-catenin in Wilms tumor patient samples that match with specific cancer properties. In this project, I aim to investigate the multiple oncogenic functions of beta-catenin in WT. The role of beta-catenin in kidney development and WT tumorigenesis is well appreciated but I hypothesize additional roles in cellular plasticity, invasion, resistance to treatment, and immune evasion. Thus, I aim to determine the entire scope of beta-catenin in WT. To this end, I will link beta-catenin activity and its role in cancer progression by combining immunofluorescence and spatial transcriptomics technologies, and I will investigate the underlying mechanisms using a molecular tracking system in 3D WT models. This will serve as a platform to test small molecules and potential new drugs that interfere with beta-catenin pro-tumoral activities. Taken together, our data will provide additional mechanistic explanation for the roles of beta-catenin in cancer progression and holds promise for the development of targeted therapies, that might ultimately not only to enhance therapeutic efficacy but also to mitigate long-term side-effects and improve overall quality of life for survivors.