Prostate cancer (PCa) is one of the most common and most heterogeneous cancers in men. The clinical course of PCa is highly variable and requires reliable prognostic markers for individualized approaches in therapy. Large scale sequencing-based studies from us (1-5) and others have previously identified the contribution of genetic and non-genetic aberrations in prostate carcinogenesis. However, the interplay of complex genomic and epigenomic alterations in the context of the extensive intra-patient tumor heterogeneity seen in PCa remain insufficiently characterized.
To address this question, we will utilize the benefits of Oxford Nanopore Technologies (ONT) long-read sequencing to simultaneously analyze structural variants and detect various epigenetic marks. ONT sequencing will be performed on spatially-resolved sections and matched lymph node metastases from high-risk treatment naïve hormone-sensitive metastatic PCa cases. These novel single fragment data are complemented by existing chromatin accessibility and transcriptome data at single-nucleus resolution (6), as well as multi-omic bulk tumor data (WGS, RNA (2, 5), and whole genome bisulfite sequencing) combined with clinical follow-up.
Our main objectives are the use of cutting-edge methods in computational multi-omics to unequivocally decipher concomitant genomic and epigenomic deregulation driving prostate cancer progression, including oncogenic enhancer hijacking events or biallelic inactivation of tumor suppressor genes, and to delineate epigenomic cell heterogeneity.
Collectively, our dataset and analysis provide a unique resource that links genomic and epigenomic alterations to the underlying cell heterogeneity in locally advanced PCa, thereby enabling us to identify aggressive pathways. These will provide new cancer-specific vulnerabilities that advance the identification of therapeutic targets in the era of precision medicine.
References:
- doi:10.1016/j.ccr.2013.01.002
- doi:10.1016/j.ccell.2018.10.016
- doi:10.1038/s41586-020-1969-6
- panprostate.org
- Gruber et al., Integrated signatures reveal dominant mutational processes in prostate cancer. Nature (in revision)
- Keshavarzian et al., Phenotypic Plasticity in Prostate Cancer Converges to Inflammatory-like States Upon Metastatic Dissemination. Nature Communications (in revision).
