Single cell analysis of cribriform prostate cancer reveals cell intrinsic and tumor microenvironmental pathways of aggressive disease.

Cribriform prostate cancer, found in both invasive cribriform carcinoma (ICC) and intraductal carcinoma (IDC), is an aggressive histological subtype that is associated with progression to lethal disease. To delineate the molecular and cellular underpinnings of ICC/IDC aggressiveness, this study examines paired ICC/IDC and benign prostate surgical samples by single-cell RNA-sequencing, TCR sequencing, and histology. ICC/IDC cancer cells express genes associated with metastasis and targets with potential for therapeutic intervention. Pathway analyses and ligand/receptor status model cellular interactions among ICC/IDC and the tumor microenvironment (TME) including JAG1/NOTCH. The ICC/IDC TME is hallmarked by increased angiogenesis and immunosuppressive fibroblasts (CTHRC1+ASPN+FAP+ENG+) along with fewer T cells, elevated T cell dysfunction, and increased C1QB+TREM2+APOE+-M2 macrophages. These findings support that cancer cell intrinsic pathways and a complex immunosuppressive TME contribute to the aggressive phenotype of ICC/IDC. These data highlight potential therapeutic opportunities to restore immune signaling in patients with ICC/IDC that may afford better outcomes.

Nature communications. 2022 Oct 13*** epublish ***

Hong Yuen Wong, Quanhu Sheng, Amanda B Hesterberg, Sarah Croessmann, Brenda L Rios, Khem Giri, Jorgen Jackson, Adam X Miranda, Evan Watkins, Kerry R Schaffer, Meredith Donahue, Elizabeth Winkler, David F Penson, Joseph A Smith, S Duke Herrell, Amy N Luckenbaugh, Daniel A Barocas, Young J Kim, Diana Graves, Giovanna A Giannico, Jeffrey C Rathmell, Ben H Park, Jennifer B Gordetsky, Paula J Hurley

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA., Department of Urology, Vanderbilt University Medical Center, Nashville, TN, USA., Vanderbilt-Ingram Cancer Center, Nashville, TN, USA., Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA., Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. .

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