Mechanisms and Therapeutic Targeting of Nuclear Shape Instability in Lethal Prostate Cancer
Abstract
This project is attempting to determine the molecular mechanisms that promote nuclear shape instability (NSI) and that produce extracellular vesicles (EVs) containing chromosomal DNA. We will determine whether EVs from prostate cancer cells contain genomic DNA. We will test the hypothesis that a novel protein driver of metastasis in drug-resistant prostate cancer, ONECUT2, will produce NSI, whether inhibiting this protein using a novel class of small molecules we developed can reverse this process, whether EVs with nuclear content are associated with aggressive prostate cancer, and test for ONECUT2 activity in blood using a novel approach. In year 1 we showed that DNA is associated with small-, medium- and large-sized EVs, suggesting that information about tumor phenotype can be derived from EVs. We have obtained evidence that ONECUT2 can operate as a pioneer factor to open chromatin. We have used in vitro models to replicate the very small nuclei (vsn) phenotype seen in circulating tumor cells from patients with advanced prostate cancer, suggesting that the vsn phenotype reflects nuclear shape instability (NSI). We obtained evidence that chromatin structure in the ONECUT2gene body may not reflect expression of the ONECUT2 gene, as originally proposed. These studies are uncovering novel connections between nuclear structure deficits and features of aggressive prostate cancer. No change in plans are anticipated for year 2.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2021
- Accession Number
- AD1163339
Entities
People
- Michael R Freeman
Organizations
- Cedars-Sinai Medical Center