Single-cell analysis of human primary prostate cancer reveals the heterogeneity of tumor-associated epithelial cell states

Hanbing Song; Hannah N W Weinstein; Paul Allegakoen; Marc H Wadsworth 2nd; Jamie Xie; Heiko Yang; Ethan A Castro; Kevin L Lu; Bradley A Stohr; Felix Y Feng; Peter R Carroll; Bruce Wang; Matthew R Cooperberg; Alex K Shalek; Franklin W Huang

doi:10.1038/s41467-021-27322-4

Single-cell analysis of human primary prostate cancer reveals the heterogeneity of tumor-associated epithelial cell states

Nat Commun. 2022 Jan 10;13(1):141. doi: 10.1038/s41467-021-27322-4.

Authors

Hanbing Song^{1

2

3

4}, Hannah N W Weinstein^#^{1

2

3

4}, Paul Allegakoen^#^{1

2

3

4}, Marc H Wadsworth 2nd^#^{5

6

7

8

9}, Jamie Xie^{1

2

3

4}, Heiko Yang^{2

10}, Ethan A Castro^{1

2

3

4}, Kevin L Lu¹¹, Bradley A Stohr¹¹, Felix Y Feng^{2

10

12}, Peter R Carroll^{2

10}, Bruce Wang¹³, Matthew R Cooperberg^{2

10

14}, Alex K Shalek^{5

6

7

8

9}, Franklin W Huang^{15

16

17

18

19}

Affiliations

¹ Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, 94143, USA.
² Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, 94143, USA.
³ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, 94143, USA.
⁴ Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, 94143, USA.
⁵ The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, 02139, USA.
⁶ Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
⁷ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
⁸ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
⁹ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA.
¹⁰ Department of Urology, University of California, San Francisco, San Francisco, CA, 94143, USA.
¹¹ Department of Pathology, University of California, San Francisco, San Francisco, CA, 94143, USA.
¹² Departments of Radiation Oncology, University of California, San Francisco, San Francisco, CA, 94143, USA.
¹³ Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, 94143, USA.
¹⁴ Division of Hematology and Oncology, Department of Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, CA, 94121, USA.
¹⁵ Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, 94143, USA. [email protected].
¹⁶ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, 94143, USA. [email protected].
¹⁷ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, 94143, USA. [email protected].
¹⁸ Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, 94143, USA. [email protected].
¹⁹ Division of Hematology and Oncology, Department of Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, CA, 94121, USA. [email protected].

^# Contributed equally.

Abstract

Prostate cancer is the second most common malignancy in men worldwide and consists of a mixture of tumor and non-tumor cell types. To characterize the prostate cancer tumor microenvironment, we perform single-cell RNA-sequencing on prostate biopsies, prostatectomy specimens, and patient-derived organoids from localized prostate cancer patients. We uncover heterogeneous cellular states in prostate epithelial cells marked by high androgen signaling states that are enriched in prostate cancer and identify a population of tumor-associated club cells that may be associated with prostate carcinogenesis. ERG-negative tumor cells, compared to ERG-positive cells, demonstrate shared heterogeneity with surrounding luminal epithelial cells and appear to give rise to common tumor microenvironment responses. Finally, we show that prostate epithelial organoids harbor tumor-associated epithelial cell states and are enriched with distinct cell types and states from their parent tissues. Our results provide diagnostically relevant insights and advance our understanding of the cellular states associated with prostate carcinogenesis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Carcinogenesis / genetics*
Carcinogenesis / metabolism
Carcinogenesis / pathology
Cell Lineage / genetics
Epithelial Cells / classification
Epithelial Cells / metabolism*
Epithelial Cells / pathology
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Ontology
Genetic Heterogeneity
Humans
Male
Molecular Sequence Annotation
Neoplasm Proteins / classification
Neoplasm Proteins / genetics*
Neoplasm Proteins / metabolism
Organoids / metabolism
Organoids / pathology
Primary Cell Culture
Prostate / metabolism
Prostate / pathology
Prostatectomy
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Prostatic Neoplasms / surgery
Signal Transduction
Single-Cell Analysis / methods
Transcriptional Regulator ERG / genetics
Transcriptional Regulator ERG / metabolism
Tumor Microenvironment / genetics*

Substances

ERG protein, human
Neoplasm Proteins
Transcriptional Regulator ERG

Grants and funding

P20 CA233255/CA/NCI NIH HHS/United States