Applying genome-scale technologies to cancer resulted in the construction of The Cancer Genome Atlas (TCGA) that provided a working taxonomy for numerous solid tumors and hematological malignancies. The recognition that cancers originating from the same organ can harbor a spectrum of oncogenic and tumor suppressor alterations between individuals led to concerted efforts to understand the diversity and frequency of pathogenic molecular features present in common human malignancies. Notably, the variation in the histological patterns are highly prognostic of PC outcomes 1, and molecular assays of gene expression also associate with recurrences following prostatectomy and radiotherapy, indicating a high degree of interindividual variation in tumor behavior 7. As observed in most solid tumors, PCs are comprised of heterogeneous populations of neoplastic cells interacting within complex ecosystems of resident cell types such as fibroblasts and vascular endothelium, infiltrating cell types including immune cells, as well as nutrients, growth factors, collagens, and other constituents that collectively contribute to an organizational framework that supports cancer cell survival and growth 6. At the time of diagnosis, biopsies often demonstrate the presence of multiple histological Gleason patterns, and independent cancer foci harbor distinct structural genomic alterations such as those involving TMPRSS2-ERG rearrangements 1, 2, 3, 4, 5. Localized prostate cancer (PC) is notable for substantial inter- and intratumor heterogeneity in both phenotype and molecular composition. Our results demonstrate the utility of DSP for accurately classifying tumor phenotype, assessing tumor heterogeneity, and identifying aspects of tumor biology involving the immunological composition of metastases. While the vast majority of metastases examined are devoid of significant inflammatory infiltrates and lack PD1, PD-L1 and CTLA4, the B7-H3/CD276 immune checkpoint protein is highly expressed, particularly in mPCs with high AR activity.

However, there are notable exceptions including tumors comprised of regions with high and low androgen receptor (AR) and neuroendocrine activity.

By assessing multiple discrete areas across multiple metastases, we find a high level of intra-patient homogeneity with respect to tumor phenotype. Here we use digital spatial profiling (DSP) technology to quantitate transcript and protein abundance in spatially-distinct regions of mPCs. However, the extent of inter- and intra-tumor heterogeneity is not established. Metastatic prostate cancer (mPC) comprises a spectrum of diverse phenotypes.

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