Abstract 3446: High-resolution mapping of human prostate tumors- guiding better risk stratification and therapeutic approaches

Abstract

Abstract Why this research is important Clinical care for localized prostate cancer in 2019 is primarily guided by a system of risk stratification that has remained unchanged for decades (PSA, tumor T-stage, Gleason grade). True advances are needed in: (1) risk stratification among primary tumors and (2) novel mechanistically rational approaches to tumors that pose the greatest clinical threat of metastatic progression. The primary prostate tumor is remarkably complex, consisting not only of tumor cells but also of extracellular matrix, vasculature, stromal cells and infiltrating immune cells. Most systemic therapies simply target the androgen receptor, a mainstay of prostate cancer therapy. Novel therapeutic targets would benefit patients with high-risk localized tumors and potentially patients with currently incurable metastatic disease. What we aim to accomplish We aim to understand, through the single-cell lens, the differences in the prostate tumor microenvironment across the spectrum of Gleason grades to identify novel cellular and molecular targets for therapeutic intervention. On the path to discovery The design of novel therapies against prostate cancer relies on a deep understanding of the identity and function of each cell type within the tumor microenvironment. Our interdisciplinary team of clinicians, surgeons, bioinformaticians and biologists will characterize changes in the cellular composition, state, and function within the prostate tumor microenvironment across the spectrum of surgical stages and grades. These efforts are largely driven by advances in single-cell sequencing and imaging technologies. Using single-cell RNA sequencing (scRNA-seq), we created the cellular anatomy of the prostate tumor and their matched-normal glandular tissues (19 patients; Gleason 6-10; T-stage 2a to 3b). We constructed an atlas comprised of ~70,000 non-erythroid viable cells collected from treatment-naïve primary prostate cancer specimens and ~75,000 cells from the matched normal prostate tissue. Analysis of transcriptional states revealed a complex tumor microenvironment, including immune cells and supporting non-immune stroma. Our analysis has allowed us to 1) create the cell-atlas of prostate tissue, 2) characterize heterogeneity of intratumoral cells of both lymphoid and myeloid cell lineages and 3) identify tumor heterogeneity among patients. We identify 8 clusters of myeloid cells and 14 clusters of lymphoid cells. A broad survey of both lineages revealed different functional states for the different clusters. Gene expression analysis will be combined with Slide- seq - a new technique that preserves the tumor architecture. Future impact of our research Our research will advance our understanding of prostate cancer biology with dual downstream goals of honing our prognostic algorithms and identifying new avenues of therapeutic intervention. Ultimately, our goal is to improve the quality and length of life of patients diagnosed with prostate cancer. Citation Format: Taghreed Hirz, Shenglin Mei, Youmna Kfoury, Chin-Lee Wu, Douglas M. Dahl, Philip Saylor, Peter Kharchenko, Ninib Baryawno, David Sykes. High-resolution mapping of human prostate tumors- guiding better risk stratification and therapeutic approaches [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3446.