Single-cell ATAC and RNA sequencing reveal pre-existing and persistent cells associated with prostate cancer relapse

S. Taavitsainen, N. Engedal, S. Cao, F. Handle, A. Erickson, S. Prekovic, D. Wetterskog, T. Tolonen, E. M. Vuorinen, A. Kiviaho, R. Nätkin, T. Häkkinen, W. Devlies, S. Henttinen, R. Kaarijärvi, M. Lahnalampi, H. Kaljunen, K. Nowakowska, H. Syvälä, M. Bläuer, P. Cremaschi, F. Claessens, T. Visakorpi, T. L. J. Tammela, T. Murtola, K. J. Granberg, A. D. Lamb, K. Ketola, I. G. Mills, G. Attard, W. Wang, M. Nykter () and A. Urbanucci ()
Additional contact information
S. Taavitsainen: Tampere University and Tays Cancer Center
N. Engedal: Oslo University Hospital
S. Cao: The University of Texas MD Anderson Cancer Center
F. Handle: Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven
A. Erickson: University of Oxford
S. Prekovic: Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute
D. Wetterskog: University College London Cancer Institute
T. Tolonen: Tampere University and Tays Cancer Center
E. M. Vuorinen: Tampere University and Tays Cancer Center
A. Kiviaho: Tampere University and Tays Cancer Center
R. Nätkin: Tampere University and Tays Cancer Center
T. Häkkinen: Tampere University and Tays Cancer Center
W. Devlies: Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven
S. Henttinen: Tampere University and Tays Cancer Center
R. Kaarijärvi: University of Eastern Finland
M. Lahnalampi: University of Eastern Finland
H. Kaljunen: University of Eastern Finland
K. Nowakowska: University College London Cancer Institute
H. Syvälä: Tampere University and Tays Cancer Center
M. Bläuer: Tampere University and Tays Cancer Center
P. Cremaschi: University College London Cancer Institute
F. Claessens: Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven
T. Visakorpi: Tampere University and Tays Cancer Center
T. L. J. Tammela: Tampere University and Tays Cancer Center
T. Murtola: Tampere University and Tays Cancer Center
K. J. Granberg: Tampere University and Tays Cancer Center
A. D. Lamb: University of Oxford
K. Ketola: University of Eastern Finland
I. G. Mills: University of Oxford
G. Attard: University College London Cancer Institute
W. Wang: The University of Texas MD Anderson Cancer Center
M. Nykter: Tampere University and Tays Cancer Center
A. Urbanucci: Oslo University Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Prostate cancer is heterogeneous and patients would benefit from methods that stratify those who are likely to respond to systemic therapy. Here, we employ single-cell assays for transposase-accessible chromatin (ATAC) and RNA sequencing in models of early treatment response and resistance to enzalutamide. In doing so, we identify pre-existing and treatment-persistent cell subpopulations that possess regenerative potential when subjected to treatment. We find distinct chromatin landscapes associated with enzalutamide treatment and resistance that are linked to alternative transcriptional programs. Transcriptional profiles characteristic of persistent cells are able to stratify the treatment response of patients. Ultimately, we show that defining changes in chromatin and gene expression in single-cell populations from pre-clinical models can reveal as yet unrecognized molecular predictors of treatment response. This suggests that the application of single-cell methods with high analytical resolution in pre-clinical models may powerfully inform clinical decision-making.

Date: 2021
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DOI: 10.1038/s41467-021-25624-1

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