Identifying the Molecular Mechanisms of Prostate Tumorigenesis Associated with Multigenic 3p13-14 Locus Loss Using a Novel CRISPR-Organoid Platform
Abstract
Human prostate cancers can feature chromosome-scale alterations, but it remains challenging to determine the causal relationship between these alterations and cancer formation. We established a mouse primary prostate organoid platform to model the large 3p13-14 locus deletion, which accounts for 15 tilde 20 percent of prostate cancer patients. We performed bulk RNA- and ATAC-seq analysis to study the role of Foxp1, a putative tumor suppressor from this region, which revealed an inflammatory response induced by Foxp1 loss and led us to study its role (and the role of the entire locus) in an immunocompetent environment. We developed a highly efficient approach to edit organoid genome through a single step which is compatible with downstream transplantation into immunocompetent hosts. Orthotopic transplantation revealed a synergistic effect between Foxp1 loss and host immune system. Together, our study provides mechanistic insight into the tumor suppressor locus and serve as a paradigm for studying other frequent chromosomal alterations in prostate cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2021
- Accession Number
- AD1154959
Entities
People
- Weiran Feng
Organizations
- Memorial Sloan Kettering Cancer Center