Abstract
Metastatic prostate cancer (mPC) comprises a spectrum of diverse phenotypes. However, the extent of inter- and intra-tumor heterogeneity is not established. Here we use digital spatial profiling (DSP) technology to quantitate transcript and protein abundance in spatially-distinct regions of mPCs. By assessing multiple discrete areas across multiple metastases, we find a high level of intra-patient homogeneity with respect to tumor phenotype. However, there are notable exceptions including tumors comprised of regions with high and low androgen receptor (AR) and neuroendocrine activity. 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. 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.
Highlights
Metastatic prostate cancer comprises a spectrum of diverse phenotypes
Tumor samples were collected over an 8-year time interval, formalin-fixed and paraffin-embedded (FFPE) at the time of resection, and stored as tumor blocks
The region of interest (ROI) captured in this study focused on regions enriched for neoplastic cells, and overall, these tumor cell rich regions were largely devoid of immune cells of any phenotype (Fig. 7a)
Summary
Metastatic prostate cancer (mPC) comprises a spectrum of diverse phenotypes. the extent of inter- and intra-tumor heterogeneity is not established. The results of TCGA for localized PC8 and further efforts involving analyses of metastatic PC identified molecular subtypes of PC with otherwise indistinguishable histological features and nominated new therapeutic targets[9,10,11,12] These studies emphasize that PC is driven by a diverse spectrum of oncogenic aberrations and provide strong rationale for personalized/precision approaches for cancer therapy. We seek to investigate the inter- and intratumor variation in gene expression using an approach termed digital spatial profiling (DSP) for quantitative, high-plex analysis of mRNAs and proteins in spatially defined regions of PC metastasis[24,25] We apply this method to the study of formalinfixed tumor biospecimens from multiple metastatic sites, including bone, acquired through rapid autopsy. In addition to assessing the variation in individual genes encoding molecular targets for specific therapeutics, we use DSP to categorize tumor phenotypes based on gene expression programs that indicate the activity of androgen receptor (AR) activity, neuroendocrine (NE) differentiation, and FGFR/MEK signaling, as well as the composition of immune cells and immunomodulatory cytokines and chemokines
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