Single Cell Analysis of Cribriform Prostate Cancer Reveals Cell Intrinsic and Tumor Microenvironmental Pathways of Aggressive Disease

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Oct 13

PMID 36229464

Authors

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

Affiliations

Soon will be listed here.

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 (CTHRC1ASPNFAPENG) along with fewer T cells, elevated T cell dysfunction, and increased C1QBTREM2APOE-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.

Citing Articles

Integrated analysis of single-cell and bulk transcriptomes uncovers clinically relevant molecular subtypes in human prostate cancer.

Ding T, He L, Lin G, Xu L, Zhu Y, Wang X Chin J Cancer Res. 2025; 37(1):90-114.

PMID: 40078560 PMC: 11893346. DOI: 10.21147/j.issn.1000-9604.2025.01.07.

CTHRC1 expresses in cancer-associated fibroblasts and is associated with resistance to anti-androgen therapy in prostate cancer.

Liang H, He Q, Wei Q, Mo Q, Yang G, Wei F Genes Genomics. 2025; .

PMID: 40009323 DOI: 10.1007/s13258-025-01624-z.

p53-loss induced prostatic epithelial cell plasticity and invasion is driven by a crosstalk with the tumor microenvironment.

Yanushko D, German Falcon B, El Bizri R, Pervizou D, Dolgos R, Keime C Cell Death Dis. 2025; 16(1):46.

PMID: 39865080 PMC: 11770131. DOI: 10.1038/s41419-025-07361-1.

Brain gliomas new transcriptomic discoveries from differentially expressed genes to therapeutic targets.

Pei S, Jiang Z, Cheng H Sci Rep. 2025; 15(1):2553.

PMID: 39833228 PMC: 11746978. DOI: 10.1038/s41598-025-86316-0.

Gold Nanoparticle Inhibits the Tumor-Associated Macrophage M2 Polarization by Inhibiting mA Methylation-Dependent ATG5/Autophagy in Prostate Cancer.

Hao Y, Duan F, Dong X, Bi R, Wang Y, Zhu S Anal Cell Pathol (Amst). 2025; 2025():6648632.

PMID: 39802931 PMC: 11724730. DOI: 10.1155/ancp/6648632.

References

Kweldam C, Wildhagen M, Steyerberg E, Bangma C, van der Kwast T, van Leenders G . Cribriform growth is highly predictive for postoperative metastasis and disease-specific death in Gleason score 7 prostate cancer. Mod Pathol. 2014; 28(3):457-64. DOI: 10.1038/modpathol.2014.116. View

Huang K, Tang Y . SChLAP1 promotes prostate cancer development through interacting with EZH2 to mediate promoter methylation modification of multiple miRNAs of chromosome 5 with a DNMT3a-feedback loop. Cell Death Dis. 2021; 12(2):188. PMC: 7884413. DOI: 10.1038/s41419-021-03455-8. View

Epstein J, Egevad L, Amin M, Delahunt B, Srigley J, Humphrey P . The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading Patterns and Proposal for a New Grading System. Am J Surg Pathol. 2015; 40(2):244-52. DOI: 10.1097/PAS.0000000000000530. View

McKenney J, Wei W, Hawley S, Auman H, Newcomb L, Boyer H . Histologic Grading of Prostatic Adenocarcinoma Can Be Further Optimized: Analysis of the Relative Prognostic Strength of Individual Architectural Patterns in 1275 Patients From the Canary Retrospective Cohort. Am J Surg Pathol. 2016; 40(11):1439-1456. DOI: 10.1097/PAS.0000000000000736. View

Mariathasan S, Turley S, Nickles D, Castiglioni A, Yuen K, Wang Y . TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018; 554(7693):544-548. PMC: 6028240. DOI: 10.1038/nature25501. View

Strell C, Paulsson J, Jin S, Tobin N, Mezheyeuski A, Roswall P . Impact of Epithelial-Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ. J Natl Cancer Inst. 2019; 111(9):983-995. PMC: 6748730. DOI: 10.1093/jnci/djy234. View

Joseph D, Henry G, Malewska A, Reese J, Mauck R, Gahan J . Single-cell analysis of mouse and human prostate reveals novel fibroblasts with specialized distribution and microenvironment interactions. J Pathol. 2021; 255(2):141-154. PMC: 8429220. DOI: 10.1002/path.5751. View

Bussemakers M, van Bokhoven A, Verhaegh G, Smit F, Karthaus H, Schalken J . DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res. 1999; 59(23):5975-9. View

Hesterberg A, Rios B, Wolf E, Tubbs C, Wong H, Schaffer K . A distinct repertoire of cancer-associated fibroblasts is enriched in cribriform prostate cancer. J Pathol Clin Res. 2021; 7(3):271-286. PMC: 8073007. DOI: 10.1002/cjp2.205. View

10.

Comito G, Giannoni E, Segura C, Barcellos-de-Souza P, Raspollini M, Baroni G . Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression. Oncogene. 2013; 33(19):2423-31. DOI: 10.1038/onc.2013.191. View

11.

Gwak J, Jeong H, Lee K, Shin J, Sim T, Na J . SFMBT2-Mediated Infiltration of Preadipocytes and TAMs in Prostate Cancer. Cancers (Basel). 2020; 12(9). PMC: 7565541. DOI: 10.3390/cancers12092718. View

12.

Zhang X, Hu L, Yang Q, Qin W, Wang X, Xu C . CTHRC1 promotes liver metastasis by reshaping infiltrated macrophages through physical interactions with TGF-β receptors in colorectal cancer. Oncogene. 2021; 40(23):3959-3973. DOI: 10.1038/s41388-021-01827-0. View

13.

Jin R, Yi Y, Yull F, Blackwell T, Clark P, Koyama T . NF-κB gene signature predicts prostate cancer progression. Cancer Res. 2014; 74(10):2763-72. PMC: 4024337. DOI: 10.1158/0008-5472.CAN-13-2543. View

14.

Hughes R, Simons B, Khan H, Miller R, Kugler V, Torquato S . Asporin Restricts Mesenchymal Stromal Cell Differentiation, Alters the Tumor Microenvironment, and Drives Metastatic Progression. Cancer Res. 2019; 79(14):3636-3650. PMC: 6734938. DOI: 10.1158/0008-5472.CAN-18-2931. View

15.

Ni W, Yang Z, Cui C, Cui Y, Fang L, Xuan Y . Tenascin-C is a potential cancer-associated fibroblasts marker and predicts poor prognosis in prostate cancer. Biochem Biophys Res Commun. 2017; 486(3):607-612. DOI: 10.1016/j.bbrc.2017.03.021. View

16.

Yost K, Satpathy A, Wells D, Qi Y, Wang C, Kageyama R . Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat Med. 2019; 25(8):1251-1259. PMC: 6689255. DOI: 10.1038/s41591-019-0522-3. View

17.

Vidal A, Duong F, Howard L, Wiggins E, Freedland S, Bhowmick N . Soluble Endoglin (sCD105) as a Novel Biomarker for Detecting Aggressive Prostate Cancer. Anticancer Res. 2020; 40(3):1459-1462. PMC: 7768804. DOI: 10.21873/anticanres.14088. View

18.

Santagata S, Demichelis F, Riva A, Varambally S, Hofer M, Kutok J . JAGGED1 expression is associated with prostate cancer metastasis and recurrence. Cancer Res. 2004; 64(19):6854-7. DOI: 10.1158/0008-5472.CAN-04-2500. View

19.

Feig C, Jones J, Kraman M, Wells R, Deonarine A, Chan D . Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013; 110(50):20212-7. PMC: 3864274. DOI: 10.1073/pnas.1320318110. View

20.

Elfandy H, Armenia J, Pederzoli F, Pullman E, Pertega-Gomes N, Schultz N . Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate. Mol Cancer Res. 2018; 17(2):446-456. PMC: 6359952. DOI: 10.1158/1541-7786.MCR-18-0440. View