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Single-cell RNA Sequencing Demonstrates Inter-Patient Heterogeneity and Altered Tumor Microenvironment in Invasive and Intraductal Cribriform Prostate Cancer

ABSTRACT: ICC and IDC are aggressive histological subtypes of prostate cancer that are associated with progression to lethal disease. To delineate cancer cell intrinsic as well as tumor microenvironmental factors that contribute to ICC/IDC aggressiveness, this study examined paired ICC/IDC-enriched and benign-enriched prostate samples obtained from radical prostatectomy (RP) by scRNAseq, TCR sequencing and histology. ICC/IDC cancer cells had robust inter-patient heterogeneity but upregulated similar pathways (MYC and TNF via NFĸB) and targets with potential for therapeutic intervention (PSMA and B7-H3). ICC/IDC was associated with increased neovasculature, and cancer foci were densely circumscribed by immunosuppressive CAF likely derived from APOD+ peri-epithelial fibroblast progenitors. The ICC/IDC TME had fewer and more dysfunctional T cells and increased M2 polarization of two macrophage subtypes compared to benign prostate. These findings support that ICC/IDC are hallmarked by several aggressive features that likely contribute to their association with lethal prostate cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE185344 | GEO | 2022/09/22

REPOSITORIES: GEO

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Project description:Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains/losses, including ETS gene fusions, PTEN loss and androgen receptor (AR) amplification, that drive prostate cancer development and progression to lethal, metastatic castrate resistant prostate cancer (CRPC)1. As less is known about the role of mutations2-4, here we sequenced the exomes of 50 lethal, heavily-pretreated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment naïve, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPC (2.00/Mb) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1, which define a subtype of ETS? prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in ~1/3 of CRPCs (commonly through TMPRSS2:ERG fusions), is a prostate cancer tumor suppressor that can also be deregulated through mutation. Further, we identified recurrent mutations in multiple chromatin/histone modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with AR, which is required for AR mediated signaling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC) , and showed that mutated FOXA1 represses androgen signaling and increases tumor growth in vitro and in vivo. Proteins that physically interact with AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX, and ASXL1 were found to be mutated in CRPC, suggesting novel drivers of prostate cancer progression and potential resistance mechanisms to anti-androgen therapies. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signaling deregulated in prostate cancer, and prioritize candidates for future study. Gene expression profiling and array CGH (aCGH) was performed on matched benign prostate tissues (n=28), localized prostate cancer (n=59), and metastatic castrate resistant prostate cancer (CRPC, n=35). For gene expression profiling, frozen prostate tissue samples (channel 2), were hybridized against a commercial pool of benign prostate tissue (Clontech, channel 1). For aCGH, frozen prostate tissue samples (channel 2) were hybridized against a commerical sample of Human Male Genomic DNA (Promega, channel 1).

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Single-cell RNA Sequencing Demonstrates Inter-Patient Heterogeneity and Altered Tumor Microenvironment in Invasive and Intraductal Cribriform Prostate Cancer

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