Role of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity

Joanna Cyrta; Anke Augspach; Maria Rosaria De Filippo; Davide Prandi; Phillip Thienger; Matteo Benelli; Victoria Cooley; Rohan Bareja; David Wilkes; Sung-Suk Chae; Paola Cavaliere; Noah Dephoure; Anne-Christine Uldry; Sophie Braga Lagache; Luca Roma; Sandra Cohen; Muriel Jaquet; Laura P Brandt; Mohammed Alshalalfa; Loredana Puca; Andrea Sboner; Felix Feng; Shangqian Wang; Himisha Beltran; Tamara Lotan; Martin Spahn; Marianna Kruithof-de Julio; Yu Chen; Karla V Ballman; Francesca Demichelis; Salvatore Piscuoglio; Mark A Rubin

doi:10.1038/s41467-020-19328-1

Role of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity

Nat Commun. 2020 Nov 3;11(1):5549. doi: 10.1038/s41467-020-19328-1.

Authors

Joanna Cyrta^{1

2}, Anke Augspach¹, Maria Rosaria De Filippo^{3

4}, Davide Prandi⁵, Phillip Thienger¹, Matteo Benelli^{5

6}, Victoria Cooley⁷, Rohan Bareja^{2

8}, David Wilkes², Sung-Suk Chae⁹, Paola Cavaliere¹⁰, Noah Dephoure^{10

11}, Anne-Christine Uldry¹², Sophie Braga Lagache¹², Luca Roma⁴, Sandra Cohen⁹, Muriel Jaquet¹, Laura P Brandt¹, Mohammed Alshalalfa¹³, Loredana Puca¹⁴, Andrea Sboner^{2

8

15

16}, Felix Feng¹², Shangqian Wang¹⁷, Himisha Beltran^{14

18}, Tamara Lotan^{19

20

21}, Martin Spahn^{22

23}, Marianna Kruithof-de Julio^{1

3

24}, Yu Chen¹⁴, Karla V Ballman⁷, Francesca Demichelis^{2

5}, Salvatore Piscuoglio^{4

25

26}, Mark A Rubin^{27

28

29}

Affiliations

¹ Department for BioMedical Research, University of Bern, 3008, Bern, Switzerland.
² The Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA.
³ Department for BioMedical Research, Urology Research Laboratory, University of Bern, 3008, Bern, Switzerland.
⁴ Institute of Pathology and Medical Genetics, University Hospital Basel, University of Basel, 4051, Basel, Switzerland.
⁵ Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38122, Trento, Italy.
⁶ Bioinformatics Unit, Hospital of Prato, 59100, Prato, Italy.
⁷ Department of Healthcare Policy and Research, Division of Biostatistics and Epidemiology, Weill Cornell Medicine, New York, NY, 10021, USA.
⁸ Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, 10021, USA.
⁹ Department of Laboratory Medicine and Pathology, Weill Cornell Medicine, New York, NY, 10021, USA.
¹⁰ Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10021, USA.
¹¹ Department of Biochemistry, Weill Cornell Medicine, New York, NY, 10021, USA.
¹² Proteomics Mass Spectrometry Core Facility, University of Bern, 3010, Bern, Switzerland.
¹³ Department of Radiation Oncology, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA.
¹⁴ Department of Medicine, Division of Medical Oncology, Weill Cornell Medicine, New York, NY, 10021, USA.
¹⁵ HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, 10021, USA.
¹⁶ Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA.
¹⁷ Human Oncology and Pathogenesis Program and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.
¹⁸ Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
¹⁹ Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²⁰ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
²¹ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
²² Lindenhofspital Bern, Prostate Center Bern, 3012, Bern, Switzerland.
²³ Department of Urology, Essen University Hospital, University of Duisburg-Essen, 47057, Essen, Germany.
²⁴ Department of Urology, Inselspital, 3010, Bern, Switzerland.
²⁵ Visceral Surgery Research Laboratory, Clarunis, Department of Biomedicine, University of Basel, 4051, Basel, Switzerland.
²⁶ Clarunis Universitäres Bauchzentrum Basel, 4002, Basel, Switzerland.
²⁷ Department for BioMedical Research, University of Bern, 3008, Bern, Switzerland. mark.rubin@dbmr.unibe.ch.
²⁸ Inselspital, 3010, Bern, Switzerland. mark.rubin@dbmr.unibe.ch.
²⁹ Bern Center for Precision Medicine, 3008, Bern, Switzerland. mark.rubin@dbmr.unibe.ch.

Abstract

Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in around 10-20% of these patients is lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data point to a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may also be relevant for other solid tumors.

Publication types

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

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / pathology
Cell Line, Tumor
Cell Lineage*
Cell Plasticity*
Chromosomal Proteins, Non-Histone / metabolism*
Cohort Studies
DNA Helicases / genetics
DNA Helicases / metabolism
Gene Expression Regulation, Neoplastic
Humans
Kaplan-Meier Estimate
Male
Models, Biological
Neoplasm Invasiveness
Neoplasm Proteins / metabolism
Neuroendocrine Tumors / metabolism
Neuroendocrine Tumors / pathology
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism*
Prostatic Neoplasms / pathology*
Protein Subunits / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcriptome / genetics

Substances

Chromosomal Proteins, Non-Histone
Neoplasm Proteins
Nuclear Proteins
Protein Subunits
SWI-SNF-B chromatin-remodeling complex
Transcription Factors
SMARCA4 protein, human
DNA Helicases

Abstract

Publication types

MeSH terms

Substances

Grants and funding