Identification of Spatial Regulatory Heterogeneity in Prostate Cancer Using Single-Nucleus Joint Profiling of Chromatin Architecture and DNA Methylation
Abstract
Rationale, Objective, and Aims: Prostate cancer is the most common non-skin cancer and the second leading cause of cancer death in men in the U.S. Although the majority of localized prostate cancer is slow-growing and manageable, the response to primary therapy is variable with ~30% of patients suffering a relapse after surgery or radiotherapy. Prostatic ductal adenocarcinoma is a rare but more aggressive form of prostate cancer and is more likely to be associated with unfavorable outcomes. Similar to other types of cancer, the genome of prostate tumor cells contains many types of mutations ranging from local DNA sequences changes to mega-scale chromosomal rearrangements. Clinical genomic studies have found that prostate tumors comprised of multiple cell populations with distinct mutation profiles are associated with worse outcomes. The genetically diverse cell populations likely enable the tumor to more easily adapt to therapeutic interventions such as androgen deprivation or radiotherapy. A key limitation of existing genomic studies of prostate cancer is that tumor samples are often analyzed without distinguishing the millions of cells that constitute the tissue, which precludes the rigorous identification of tumor cell populations associated with distinct genomic rearrangements and epigenomic characteristics. The epigenome consists of chemical modifications of the human genome, such as cytosine methylation, and plays a vital role in the regulation of gene expression in normal tissue functions and diseases including cancer. It is well known that tumor cells are associated with profound abnormalities of cytosine methylation patterns, including excessive methylation at tumor suppressor genes, and mega-scale under-methylation genomic regions called partially methylated domains. In this proposed project, we will distinguish single prostate tumor cells with distinct genomic and epigenomic characteristics, with a focus on the more aggressive prostatic ductal adenocarcinoma. We will apply a cutting-edge technique named sn-m3C-seq to jointly profile the genome-wide pattern of chromatin conformation and cytosine methylation in single cells. Using this novel type of genomic data, we will identify genetic and epigenomic markers of prostate cancer that are only present in a subset of cell populations and were likely overlooked by traditional genomic analysis approaches. Applicability of the Research: Our project will contribute to PCRP Overarching Challenges by revealing novel aspects of cancer biology for an aggressive type of prostate cancer-prostatic ductal adenocarcinoma, with respect to genomic rearrangement, DNA methylation, and chromatin conformation. Results from the proposed project may be clinically applied by generating novel genomic biomarkers such as chromosomal rearrangement that can be further developed and validated to predict aggressiveness from indolent tumors, in the next 3-5 years. Such application would benefit men with early-stage tumors deciding between treatment strategies by improving the prediction of tumor aggressiveness using novel genetic markers identified in the proposed study.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210569
Entities
People
- Chongyuan Luo
Organizations
- United States Army
- University of California, Los Angeles