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Mechanisms of Androgen Receptor-Independent Pathways for Lineage Plasticity in Prostate Cancer
Korea (KMSA) - Korea university, Seoul
Department of Biomedical Sciences
Type of Research Project
- Basic science
What is the background of the project?
Prostate cancer is the second leading cause of cancer-related death in men. In 1941, Charles Huggins’ remarkable discovery established androgen deprivation by surgical castration as a beneficial intervention in the treatment of advanced prostate cancer. These seminal studies provided the framework for a paradigm-shift in using gonadotropin-releasing hormone agonists or antagonists for chronic chemical castration. While nearly all prostate cancer patients respond to hormonal therapy, there is a uniform progression to castration-resistant disease (CRPC). CRPC was though to develop from residual post-chemical-castration androgen levels as well as persistent activation of androgen receptor (AR). This led to the discovery and subsequent FDA-approval of second-generation anti-androgen therapies, including abiraterone and enzalutamide. However, despite the success of these AR-directed therapies, resistance invariably develops posing an ongoing clinical dilemma. Mechanisms of secondary resistance include restored AR signaling, AR-bypass signaling through pathways. The latter form of resistance arises from lineage plasticity, which is characterized by the transition of luminal epithelial cells to basal epithelial mesenchymal and neuroendocrine cells. Genomic analysis of a cohort of metastatic CRPC patients has revealed amplification and mutation of the AR in 60% cases, suggesting AR-dependence in this large subset. However, the cohort also harbored a mutation or deletion of TP53 with a loss of RB1 is a smaller subset. These latter patients with TP53 and RB1 co-deletion also lost AR expression and activity indicative of an AR-independent pathway, with 75% displaying a neuroendocrine histology. Another avenue for understanding lineage plasticity has focused on identifying the cell type in the normal prostate that initiates cancer – the cell of its origin. There is a growing body of evidence for the existence of a minor subpopulation of AR-independent cells within prostate cancer that may have a selective advantage over AR-dependent subpopulations that respond to anti-androgen therapy.
What is the aim of the project?
To gain further insights into the cell of origin of prostate cancer and to study the potential modulatory role of non-epithelial lineages within the tumor microenvironment (TME) in determining lineage plasticity.
What techniques and methods are used?
Our approach relies on cutting-edge technology such as single cell RNA sequencing (scRNA-Seq) and an assay for transposase-accessible chromatin sequencing (ATAC-Seq) to further delineate precise transcriptome and epigenetic alterations in luminal and basal epithelial cells as well as in non-epithelial cells across castration and androgen add-back.
What is the role of the student?
- The student will observe the practical experiments but will be highly involved in the analysis of the results
What are the tasks expected to be accomplished by the student?
The student will perform scRNA-Seq and ATAC-Seq on a known model of AR-dependent, castrate-resistant prostate cancer to identify genetic and epigenetic pathways underlying the transition of luminal epithelial cells to basal epithelial, mesenchymal or neuroendocrine cells. Prostate organoids derived from Tp53-/- and Rb1-/- mice that are infected with Cre-expressing lentivirus will be used. The samples will be sequenced in triplicate and bioinformatic analyses will be performed using standard pipeline such as Seurat and Scanpy. The student will also seek to identify the cell of origin for prostate cancer through scRNA-Seq and ATAC-Seq performed on the Tp53/Tb1 genetically modified mouse model in response to castration and androgen add-back. The student will also explore the contribution of non-epithelial cell lineages in the TME, in particular tumor-associated macrophages (TAMs) in enabling lineage plasticity. The student will apply appropriate bioinformatic tools to study transcriptome and cistome data obtaining from scRNA-Seq and ATAC-Seq. Finally, the student will obtain clues for preventing anti-androgen resistance which would form the premise for further studies on pharmacologic targeting.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
The student will be given a numerous chance to attend the seminars and journal clubs in the college.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- No specific outcome is expected
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
Willingness to learn computer languages such as R and python
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months) - Pre-Medical students from the American-British system - Students in biomedical fields - Dental medicine students (IADS members)
- Adams; E.J.; Karthaus; W.R.; Hoover; E. et al. FOXA1 mutations alter pioneering activity; differentiation and prostate cancer phenotypes. Nature 571; 408–412 (2019) doi:10.1038/s41586-019-1318-9
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