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

Author

Listed:
  • Hong Yuen Wong

    (Vanderbilt University Medical Center)

  • Quanhu Sheng

    (Vanderbilt University Medical Center)

  • Amanda B. Hesterberg

    (Vanderbilt University Medical Center)

  • Sarah Croessmann

    (Vanderbilt University Medical Center)

  • Brenda L. Rios

    (Vanderbilt University Medical Center)

  • Khem Giri

    (Vanderbilt University Medical Center)

  • Jorgen Jackson

    (Vanderbilt University Medical Center)

  • Adam X. Miranda

    (Vanderbilt University Medical Center)

  • Evan Watkins

    (Vanderbilt University Medical Center)

  • Kerry R. Schaffer

    (Vanderbilt University Medical Center
    Vanderbilt-Ingram Cancer Center)

  • Meredith Donahue

    (Vanderbilt University Medical Center)

  • Elizabeth Winkler

    (Vanderbilt University Medical Center)

  • David F. Penson

    (Vanderbilt-Ingram Cancer Center
    Vanderbilt University Medical Center)

  • Joseph A. Smith

    (Vanderbilt University Medical Center)

  • S. Duke Herrell

    (Vanderbilt University Medical Center)

  • Amy N. Luckenbaugh

    (Vanderbilt University Medical Center)

  • Daniel A. Barocas

    (Vanderbilt University Medical Center)

  • Young J. Kim

    (Vanderbilt-Ingram Cancer Center
    Vanderbilt University Medical Center
    Regeneron Pharmaceuticals, Tarrytown)

  • Diana Graves

    (Vanderbilt University Medical Center)

  • Giovanna A. Giannico

    (Vanderbilt University Medical Center)

  • Jeffrey C. Rathmell

    (Vanderbilt-Ingram Cancer Center
    Vanderbilt University Medical Center
    Vanderbilt Center for Immunobiology)

  • Ben H. Park

    (Vanderbilt University Medical Center
    Vanderbilt-Ingram Cancer Center)

  • Jennifer B. Gordetsky

    (Vanderbilt-Ingram Cancer Center
    Vanderbilt University Medical Center)

  • Paula J. Hurley

    (Vanderbilt University Medical Center
    Vanderbilt-Ingram Cancer Center
    Vanderbilt University Medical Center)

Abstract

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.

Suggested Citation

  • 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 & Elizabet, 2022. "Single cell analysis of cribriform prostate cancer reveals cell intrinsic and tumor microenvironmental pathways of aggressive disease," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33780-1
    DOI: 10.1038/s41467-022-33780-1
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