Project Summary
Earlier gains in reducing prostate cancer (PCa) mortality, partially due to advances in screening and the use of
androgen deprivation therapy to treat metastatic PCa (mPCa), have not been sustained in recent years. Current
clinical and research challenges include overtreatment of patients with low probability of progression, no effective
therapy for metastatic castration-resistant PCa (mCRPC), and the persistent health disparities in PCa for
African American men. A better understanding of the molecular dynamics and interactions among cancer and
non-cancer cells within the tumor microenvironment CTME) at high resolution and in a spatial context across time
will be crucial for addressing these challenges. Against the backdrop of recent advances in multi-omics and
spatial technologies, we propose to use our expertise in the latest technological platforms, experience in atlas
building, and strengths in PCa research and treatment at Washington University School of Medicine (WUSM) to
extend our prior HTAN work to PCa. The proposed Human Prostate Tumor Atlas Center (HPTAC) will elucidate
PCa architecture, cellular dynamics, TME interactions, and temporal evolution via the building of a molecularly
resolved spatial atlas that integrates multi-omics, imaging, and clinical data, with a focus on spatial
characterization with maximum optical display of molecular and cellular features. We will procure both
retrospective and prospective PCa specimens with detailed clinical data at WUSM, which maintains a
comprehensive repository of PCa specimens and has a high PCa patient volume (Aim 1). These specimens will
span two critical transitions: from indolent to aggressive PCa and from hormone-sensitive to castration-resistant
metastatic PCa. The high percentage of African American patients in our PCa patient population permits a 50%
composition of African American specimens to investigate the biological basis for disparities associated with
African ancestry. Aim 2 concentrates on molecular and spatial characterization of PCa specimens. At the core
of the spatial characterization are spatial-omics, including sequencing-based (Visium/Curio Seeker) and
imaging-based (Xenium/CosMx) platforms, 2D/3D imaging modalities, including CODEX, 3D in vitro Light Sheet
Fluorescence Microscopy, and in vivo MRI/DBSI imaging. These technologies will be augmented by bulk and
single cell omics for mutations/ancestry detection and overall molecular profiling. In Aim 3, data will be analyzed
and integrated into a molecularly resolved spatial atlas of PCa. Co-registration, reconstruction, and integration
will be achieved by employing computational tools, such as PASTE2, Morph, Mushroom. The resulting atlas will
describe molecular, cellular, and spatiotemporal relationships of cellular and non-cellular components of the PCa
ecosystem across critical transitions. In Aim 4, we will establish a collaborative infrastructure within our HPTAC
and foster collaborations across HTAN centers. Data will be deposited with the HTAN Data Coordination Center
in accordance with FAIR standards. Methodologies developed in, and findings from this study will have broad
impact on atlas building for other cancers and on addressing some of the most pressing challenges in PCa.