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

Author:

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

Abstract

AbstractCribriform 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.

Funder

U.S. Department of Health & Human Services | National Institutes of Health

U.S. Department of Health & Human Services | NIH | National Cancer Institute

American Cancer Society

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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