CORE 1, SYSTEMS PATHOLOGY – SUMMARY Sex differences in cancer risk, incidence, therapeutic response, and outcomes are well-known but poorly understood. Sex disparities relating to bladder cancers involves an interplay between sex chromosomes, sex hormones, and tumor micro-environment, including the immune cells and epigenomic alterations. The overarching goal of the Systems Pathology Core (Core 1) is to support Program investigators by providing streamlined and harmonized collection, processing and analysis of human and murine biospecimens to achieve the aims outlined in the Program projects. This core will be co-led by Dr. Anil Parwani (The Ohio State University Wexner Medical Center [OSUMC]) and Dr. Sergei Grivennikov (Cedars-Sinai Medical Center [CSMC]) and will provide coordinated services for this multi-institutional Program. To accomplish core goals and avoid duplication of services, Core 1 will work closely with resources at OSU, including the Comparative Pathology and Digital Imaging Shared Resource, the Pathology Department, the Immune Monitoring and Discovery Platform, and the Cooperative Human Tissue Network Midwestern network. At CSMC, Core 1 will utilize resources in the Flow Cytometry, Advanced Genomics, and Mass Cytometry Shared Resources as well as Biobank Translational Research Core. The specific aims and services for the Systems Pathology Core are: Specific Aim 1. Act as a high-quality biorepository to collect, process, bank, and distribute annotated human and murine bladder cancer specimens and their derivatives for Program research. Specific Aim 2. Provide histology and pathology services to analyze human and murine bladder cancer biospecimens using immunohistochemistry and immunofluorescence with pathological characterization and spatial mapping (via Co-Detection by Indexing [CODEX]). This core will also provide pathologist diagnostic consultation, project planning, method development, scoring, interpretation, and manuscript writing. Specific Aim 3. Provide flow cytometry and single cell analysis services including multiparameter flow cytometry analysis and sorting, single cell RNA sequencing (scRNAseq), Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITEseq), Assay for Transposase-Accessible Chromatin using sequencing (ATACseq), mass cytometry (CyTOF), and standard molecular analyses. The core will harmonize processing and analysis techniques across Program sites to ensure data integrity and unified results. The Systems Pathology Core will work closely with the Administrative Core and the Data Science Core, which will provide robust data management and analysis of the data acquired herein.