Dynamics in lineage plasticity (Dr. Irene Paassen, Postdoc)
Treatment resistance in prostate cancer (PCa) is an emerging problem worldwide due to increasing numbers of diagnoses. Development of targeted therapies for PCa, lead to the outgrowth of resistant tumors with altered lineage identity compared to pre-treatment tumors. The cellular and molecular mechanisms that underlie treatment-associated lineage transitioning remain poorly understood. Growing evidence suggests that epigenetic regulation may play an essential role. One major determinant of cell identity in both, disease and development, is the SWI/SNF chromatin remodeler complex. In this project we aim to elucidate its role controlling lineage transition in PCa.
We will utilize RPM (= Rb1-/-; Trp53-/-; MycT58A) PCa organoids, which recapitulate lineage transitioning in vivo toward a treatment-resistant PCa subtype. A barcoded CRISPR screen targeting subunits and targets of the SWI/SNF complex for gene-knockout will be performed in this model system. Following subcutaneous injection of barcoded organoids into mice, tumors will be extracted at multiple time points and analyzed using combined single-cell RNA and ATAC-sequencing. The use of state-of-the-art technologies on this unique model system will provide novel insights into the SWI/SNF-controlled chromatin landscape and clonal dynamics underlying lineage transition in PCa.
This project is supported by the US Department of Defense and the Wilhelm Sander Stiftung.
