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1. Single cell and spatial transcriptomics highlight the interaction of club-like cells with immunosuppressive myeloid cells in prostate cancer

Author

Antti Kiviaho, Sini K. Eerola, Heini M. L. Kallio, Maria K. Andersen, Miina Hoikka, Aliisa M. Tiihonen, Iida Salonen, Xander Spotbeen, Alexander Giesen, Charles T. A. Parker, Sinja Taavitsainen, Olli Hantula, Mikael Marttinen, Ismaïl Hermelo, Mazlina Ismail, Elise Midtbust, Maximilian Wess, Wout Devlies, Abhibhav Sharma, Sebastian Krossa, Tomi Häkkinen, Ebrahim Afyounian, Katy Vandereyken, Sam Kint, Juha Kesseli, Teemu Tolonen, Teuvo L. J. Tammela, Trond Viset, Øystein Størkersen, Guro F. Giskeødegård, Morten B. Rye, Teemu Murtola, Andrew Erickson, Leena Latonen, G. Steven Bova, Ian G. Mills, Steven Joniau, Johannes V. Swinnen, Thierry Voet, Tuomas Mirtti, Gerhardt Attard, Frank Claessens, Tapio Visakorpi, Kirsi J. Rautajoki, May-Britt Tessem, Alfonso Urbanucci, and Matti Nykter

Subjects
Science
Abstract

Abstract Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics data from 120 patients. We identify club-like cells as a key epithelial cell subtype that acts as an interface between the prostate and the immune system. Tissue areas enriched with club-like cells have depleted androgen signaling and upregulated expression of luminal progenitor cell markers. Club-like cells display a senescence-associated secretory phenotype and their presence is linked to increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity. Our results indicate that club-like cells are associated with myeloid inflammation previously linked to androgen deprivation therapy resistance, providing a rationale for their therapeutic targeting.

Published
2024
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2. Single cell and spatial transcriptomics highlight the interaction of club-like cells with immunosuppressive myeloid cells in prostate cancer

Author

Kiviaho, Antti, Eerola, Sini K., Kallio, Heini M. L., Andersen, Maria K., Hoikka, Miina, Tiihonen, Aliisa M., Salonen, Iida, Spotbeen, Xander, Giesen, Alexander, Parker, Charles T. A., Taavitsainen, Sinja, Hantula, Olli, Marttinen, Mikael, Hermelo, Ismaïl, Ismail, Mazlina, Midtbust, Elise, Wess, Maximilian, Devlies, Wout, Sharma, Abhibhav, Krossa, Sebastian, Häkkinen, Tomi, Afyounian, Ebrahim, Vandereyken, Katy, Kint, Sam, Kesseli, Juha, Tolonen, Teemu, Tammela, Teuvo L. J., Viset, Trond, Størkersen, Øystein, Giskeødegård, Guro F., Rye, Morten B., Murtola, Teemu, Erickson, Andrew, Latonen, Leena, Bova, G. Steven, Mills, Ian G., Joniau, Steven, Swinnen, Johannes V., Voet, Thierry, Mirtti, Tuomas, Attard, Gerhardt, Claessens, Frank, Visakorpi, Tapio, Rautajoki, Kirsi J., Tessem, May-Britt, Urbanucci, Alfonso, and Nykter, Matti

Published
2024
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3. Estimation of tumor cell total mRNA expression in 15 cancer types predicts disease progression

Author

Cao, Shaolong, Wang, Jennifer R, Ji, Shuangxi, Yang, Peng, Dai, Yaoyi, Guo, Shuai, Montierth, Matthew D, Shen, John Paul, Zhao, Xiao, Chen, Jingxiao, Lee, Jaewon James, Guerrero, Paola A, Spetsieris, Nicholas, Engedal, Nikolai, Taavitsainen, Sinja, Yu, Kaixian, Livingstone, Julie, Bhandari, Vinayak, Hubert, Shawna M, Daw, Najat C, Futreal, P Andrew, Efstathiou, Eleni, Lim, Bora, Viale, Andrea, Zhang, Jianjun, Nykter, Matti, Czerniak, Bogdan A, Brown, Powel H, Swanton, Charles, Msaouel, Pavlos, Maitra, Anirban, Kopetz, Scott, Campbell, Peter, Speed, Terence P, Boutros, Paul C, Zhu, Hongtu, Urbanucci, Alfonso, Demeulemeester, Jonas, Van Loo, Peter, and Wang, Wenyi

Subjects
Human Genome, Genetics, Cancer, 2.1 Biological and endogenous factors, Aetiology, Humans, Neoplasms, Genetic Heterogeneity, Genomics, RNA, Messenger, Disease Progression
Abstract

Single-cell RNA sequencing studies have suggested that total mRNA content correlates with tumor phenotypes. Technical and analytical challenges, however, have so far impeded at-scale pan-cancer examination of total mRNA content. Here we present a method to quantify tumor-specific total mRNA expression (TmS) from bulk sequencing data, taking into account tumor transcript proportion, purity and ploidy, which are estimated through transcriptomic/genomic deconvolution. We estimate and validate TmS in 6,590 patient tumors across 15 cancer types, identifying significant inter-tumor variability. Across cancers, high TmS is associated with increased risk of disease progression and death. TmS is influenced by cancer-specific patterns of gene alteration and intra-tumor genetic heterogeneity as well as by pan-cancer trends in metabolic dysregulation. Taken together, our results indicate that measuring cell-type-specific total mRNA expression in tumor cells predicts tumor phenotypes and clinical outcomes.

Published
2022

4. Androgen regulation of the androgen receptor coregulators

Author

Helenius Merja A, Suikki Hanna E, Waltering Kati K, Urbanucci Alfonso, and Visakorpi Tapio

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background The critical role of the androgen receptor (AR) in the development of prostate cancer is well recognized. The transcriptional activity of AR is partly regulated by coregulatory proteins. It has been suggested that these coregulators could also be important in the progression of prostate cancer. The aim of this study was to identify coregulators whose expression is regulated by either the androgens and/or by the expression level of AR. Methods We used empty vector and AR cDNA-transfected LNCaP cells (LNCaP-pcDNA3.1, and LNCaP-ARhi, respectively), and grew them for 4 and 24 hours in the presence of dihydrotestosterone (DHT) at various concentrations. The expression of 25 AR coregulators (SRC1, TIF2, PIAS1, PIASx, ARIP4, BRCA1, β-catenin, AIB3, AIB1, CBP, STAT1, NCoR1, AES, cyclin D1, p300, ARA24, LSD1, BAG1L, gelsolin, prohibitin, JMJD2C, JMJD1A, MAK, PAK6 and MAGE11) was then measured by using real-time quantitative RT-PCR (Q-RT-PCR). Results Five of the coregulators (AIB1, CBP, MAK, BRCA1 and β-catenin) showed more than 2-fold induction and 5 others (cyclin D1, gelsolin, prohibitin, JMJD1A, and JMJD2C) less than 2-fold induction. Overexpression of AR did not affect the expression of the coregulators alone. However, overexpression of AR enhanced the DHT-stimulated expression of MAK, BRCA1, AIB1 and CBP and reduced the level of expression of β-catenin, cyclinD1 and gelsolin. Conclusion In conclusion, we identified 5 coactivators whose expression was induced by androgens suggesting that they could potentiate AR signaling. Overexpression of AR seems to sensitize cells for low levels of androgens.

Published
2008
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5. Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories.

Author

Gerhauser, Clarissa, Favero, Francesco, Risch, Thomas, Simon, Ronald, Feuerbach, Lars, Assenov, Yassen, Heckmann, Doreen, Sidiropoulos, Nikos, Waszak, Sebastian M, Hübschmann, Daniel, Urbanucci, Alfonso, Girma, Etsehiwot G, Kuryshev, Vladimir, Klimczak, Leszek J, Saini, Natalie, Stütz, Adrian M, Weichenhan, Dieter, Böttcher, Lisa-Marie, Toth, Reka, Hendriksen, Josephine D, Koop, Christina, Lutsik, Pavlo, Matzk, Sören, Warnatz, Hans-Jörg, Amstislavskiy, Vyacheslav, Feuerstein, Clarissa, Raeder, Benjamin, Bogatyrova, Olga, Schmitz, Eva-Maria, Hube-Magg, Claudia, Kluth, Martina, Huland, Hartwig, Graefen, Markus, Lawerenz, Chris, Henry, Gervaise H, Yamaguchi, Takafumi N, Malewska, Alicia, Meiners, Jan, Schilling, Daniela, Reisinger, Eva, Eils, Roland, Schlesner, Matthias, Strand, Douglas W, Bristow, Robert G, Boutros, Paul C, von Kalle, Christof, Gordenin, Dmitry, Sültmann, Holger, Brors, Benedikt, Sauter, Guido, Plass, Christoph, Yaspo, Marie-Laure, Korbel, Jan O, Schlomm, Thorsten, and Weischenfeldt, Joachim

Subjects
Humans, Prostatic Neoplasms, RNA-Binding Proteins, Risk Factors, Evolution, Molecular, DNA Methylation, Gene Expression Regulation, Neoplastic, Mutation, Adult, Middle Aged, Male, Transcriptome, Biomarkers, Tumor, Whole Genome Sequencing, APOBEC, cancer genomics, early-onset cancer, epigenetic risk-score, mutational processes, prostate cancer, structural variants, tumor evolution, tumor evolution prediction, Human Genome, Aging, Prevention, Cancer, Urologic Diseases, Prostate Cancer, Genetics, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, 2.1 Biological and endogenous factors, Detection, screening and diagnosis, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples.

Published
2018

6. Androgen deprivation therapy-resistant club cells are linked to myeloid cell-driven immunosuppression in the prostate tumor microenvironment

Author

Kiviaho, Antti, primary, Eerola, Sini K., additional, Kallio, Heini M.L., additional, Andersen, Maria K., additional, Spotbeen, Xander, additional, Giesen, Alexander, additional, Parker, Charles T.A., additional, Taavitsainen, Sinja, additional, Hantula, Olli, additional, Marttinen, Mikael, additional, Hermelo, Ismaïl, additional, Ismail, Mazlina, additional, Midtbust, Elise, additional, Wess, Maximilian, additional, Devlies, Wout, additional, Sharma, Abhibhav, additional, Krossa, Sebastian, additional, Häkkinen, Tomi, additional, Afyounian, Ebrahim, additional, Kesseli, Juha, additional, Tolonen, Teemu, additional, Tammela, Teuvo L.J., additional, Viset, Trond, additional, Størkersen, Øystein, additional, Giskeødegård, Guro F., additional, Rye, Morten B., additional, Murtola, Teemu, additional, Latonen, Leena, additional, Bova, G. Steven, additional, Mills, Ian G., additional, Joniau, Steven, additional, Swinnen, Johannes V., additional, Mirtti, Tuomas, additional, Attard, Gerhardt, additional, Claessens, Frank, additional, Visakorpi, Tapio, additional, Rautajoki, Kirsi J., additional, Tessem, May-Britt, additional, Urbanucci, Alfonso, additional, and Nykter, Matti, additional

Published
2024
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7. Single-cell ATAC and RNA sequencing reveal pre-existing and persistent cells associated with prostate cancer relapse

Author

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

Subjects
Science
Abstract

Identifying the molecular mechanisms of response to systemic therapy in prostate cancer remains crucial. Here, the authors apply single cell-ATAC and RNAseq to models of early treatment response and resistance to enzalutamide and identify chromatin and gene expression patterns that can predict treatment response.

Published
2021
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8. Measuring Autophagic Cargo Flux with Keima-Based Probes

Author

Engedal, Nikolai, primary, Sønstevold, Tonje, additional, Beese, Carsten J., additional, Selladurai, Sarvini, additional, Melcher, Thea, additional, Simensen, Julia E., additional, Frankel, Lisa B., additional, Urbanucci, Alfonso, additional, and Torgersen, Maria L., additional

Published
2022
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9. Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

Author

Urbanucci, Alfonso, Barfeld, Stefan J, Kytölä, Ville, Itkonen, Harri M, Coleman, Ilsa M, Vodák, Daniel, Sjöblom, Liisa, Sheng, Xia, Tolonen, Teemu, Minner, Sarah, Burdelski, Christoph, Kivinummi, Kati K, Kohvakka, Annika, Kregel, Steven, Takhar, Mandeep, Alshalalfa, Mohammed, Davicioni, Elai, Erho, Nicholas, Lloyd, Paul, Karnes, R Jeffrey, Ross, Ashley E, Schaeffer, Edward M, Griend, Donald J Vander, Knapp, Stefan, Corey, Eva, Feng, Felix Y, Nelson, Peter S, Saatcioglu, Fahri, Knudsen, Karen E, Tammela, Teuvo LJ, Sauter, Guido, Schlomm, Thorsten, Nykter, Matti, Visakorpi, Tapio, and Mills, Ian G

Subjects
Biological Sciences, Urologic Diseases, Prostate Cancer, Aging, Genetics, Cancer, 2.1 Biological and endogenous factors, Aetiology, ATPases Associated with Diverse Cellular Activities, Chromatin, Chromatin Assembly and Disassembly, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Humans, Male, Neoplasm Proteins, Prostatic Neoplasms, Castration-Resistant, Protein Serine-Threonine Kinases, Receptors, Androgen, Transcription Factors, ATAD2, BRD2, BRD4, BROMO-10, androgen receptor, bromodomain inhibitor, castration-resistant prostate cancer, chromatin, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract

Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.

Published
2017

10. Cell cycle-coupled expansion of AR activity promotes cancer progression

Author

McNair, C, Urbanucci, A, Comstock, CES, Augello, MA, Goodwin, JF, Launchbury, R, Zhao, SG, Schiewer, MJ, Ertel, A, Karnes, J, Davicioni, E, Wang, L, Wang, Q, Mills, IG, Feng, FY, Li, W, Carroll, JS, and Knudsen, KE

Subjects
Clinical Research, Clinical Trials and Supportive Activities, Urologic Diseases, Prostate Cancer, Cancer, Stem Cell Research - Nonembryonic - Non-Human, Stem Cell Research, Aetiology, 2.1 Biological and endogenous factors, Androgens, Base Sequence, Binding Sites, Cell Cycle, Cluster Analysis, Computational Biology, Disease Progression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Models, Biological, Neoplasms, Nucleotide Motifs, Phenotype, Prognosis, Protein Binding, Receptors, Androgen, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

The androgen receptor (AR) is required for prostate cancer (PCa) survival and progression, and ablation of AR activity is the first line of therapeutic intervention for disseminated disease. While initially effective, recurrent tumors ultimately arise for which there is no durable cure. Despite the dependence of PCa on AR activity throughout the course of disease, delineation of the AR-dependent transcriptional network that governs disease progression remains elusive, and the function of AR in mitotically active cells is not well understood. Analyzing AR activity as a function of cell cycle revealed an unexpected and highly expanded repertoire of AR-regulated gene networks in actively cycling cells. New AR functions segregated into two major clusters: those that are specific to cycling cells and retained throughout the mitotic cell cycle ('Cell Cycle Common'), versus those that were specifically enriched in a subset of cell cycle phases ('Phase Restricted'). Further analyses identified previously unrecognized AR functions in major pathways associated with clinical PCa progression. Illustrating the impact of these unmasked AR-driven pathways, dihydroceramide desaturase 1 was identified as an AR-regulated gene in mitotically active cells that promoted pro-metastatic phenotypes, and in advanced PCa proved to be highly associated with development of metastases, recurrence after therapeutic intervention and reduced overall survival. Taken together, these findings delineate AR function in mitotically active tumor cells, thus providing critical insight into the molecular basis by which AR promotes development of lethal PCa and nominate new avenues for therapeutic intervention.

Published
2017

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

Author

Taavitsainen, S., Engedal, N., Cao, S., Handle, F., Erickson, A., Prekovic, S., Wetterskog, D., Tolonen, T., Vuorinen, E. M., Kiviaho, A., Nätkin, R., Häkkinen, T., Devlies, W., Henttinen, S., Kaarijärvi, R., Lahnalampi, M., Kaljunen, H., Nowakowska, K., Syvälä, H., Bläuer, M., Cremaschi, P., Claessens, F., Visakorpi, T., Tammela, T. L. J., Murtola, T., Granberg, K. J., Lamb, A. D., Ketola, K., Mills, I. G., Attard, G., Wang, W., Nykter, M., and Urbanucci, A.

Published
2021
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21. c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks

Author

Stefan J. Barfeld, Alfonso Urbanucci, Harri M. Itkonen, Ladan Fazli, Jessica L. Hicks, Bernd Thiede, Paul S. Rennie, Srinivasan Yegnasubramanian, Angelo M. DeMarzo, and Ian G. Mills

Subjects
Prostate cancer, Glycine N-Methyltransferase (GNMT), Chromatin immunoprecipitation exonuclease (ChIP-exo), Androgen receptor, c-Myc, DNA damage, Medicine, Medicine (General), R5-920
Abstract

Prostate cancer (PCa) is the most common non-cutaneous cancer in men. The androgen receptor (AR), a ligand-activated transcription factor, constitutes the main drug target for advanced cases of the disease. However, a variety of other transcription factors and signaling networks have been shown to be altered in patients and to influence AR activity. Amongst these, the oncogenic transcription factor c-Myc has been studied extensively in multiple malignancies and elevated protein levels of c-Myc are commonly observed in PCa. Its impact on AR activity, however, remains elusive. In this study, we assessed the impact of c-Myc overexpression on AR activity and transcriptional output in a PCa cell line model and validated the antagonistic effect of c-MYC on AR-targets in patient samples. We found that c-Myc overexpression partially reprogrammed AR chromatin occupancy and was associated with altered histone marks distribution, most notably H3K4me1 and H3K27me3. We found c-Myc and the AR co-occupy a substantial number of binding sites and these exhibited enhancer-like characteristics. Interestingly, c-Myc overexpression antagonised clinically relevant AR target genes. Therefore, as an example, we validated the antagonistic relationship between c-Myc and two AR target genes, KLK3 (alias PSA, prostate specific antigen), and Glycine N-Methyltransferase (GNMT), in patient samples. Our findings provide unbiased evidence that MYC overexpression deregulates the AR transcriptional program, which is thought to be a driving force in PCa.

Published
2017
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22. ABI1 regulates transcriptional activity of Androgen Receptor by novel DNA and AR binding mechanism

Author

Porter, Baylee A., primary, Li, Xiang, additional, Arya, Neeru, additional, Zhang, Fan, additional, Kung, Sonia H.Y., additional, Fazli, Ladan, additional, Zarni Oo, Htoo, additional, Li, Yinan, additional, Marincin, Kenneth, additional, Kukkonen, Konsta, additional, Urhonen, Henna, additional, Ortiz, Maria A., additional, Kemraj, Allysa P., additional, Corey, Eva, additional, Dong, Xuesen, additional, Kuznetsov, Vladimir A., additional, Nykter, Matti, additional, Gleave, Martin E., additional, Bratslavsky, Gennady, additional, Urbanucci, Alfonso, additional, Frueh, Dominique, additional, Bah, Alaji, additional, and Kotula, Leszek, additional

Published
2023
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23. Abstract 5644: Spatially resolved transcriptomics points to distinct malignant cell populations within primary and castration resistant prostate cancer

Author

Kiviaho, Antti, primary, Kallio, Heini M., additional, Eerola, Sini K., additional, Vuorinen, Elisa M., additional, Häkkinen, Tomi, additional, Taavitsainen, Sinja, additional, Afyounian, Ebrahim, additional, Tolonen, Teemu, additional, Kesseli, Juha, additional, Urbanucci, Alfonso, additional, Rautajoki, Kirsi J., additional, Tammela, Teuvo L., additional, Visakorpi, Tapio, additional, and Nykter, Matti, additional

Published
2023
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24. Supplementary Figure 1 from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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25. Supplementary Figure 6 from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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27. Supplementary Data from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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28. Supplementary Figure 7 from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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29. Supplementary Figure 5 from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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30. Data from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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31. Supplementary Figure 2 from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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32. Supplementary Figure 4 from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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33. Supplementary Data, Supplementary Figures and Legends 1-13 from Inhibition of O-GlcNAc Transferase Renders Prostate Cancer Cells Dependent on CDK9

Author

Itkonen, Harri M., primary, Poulose, Ninu, primary, Steele, Rebecca E., primary, Martin, Sara E.S., primary, Levine, Zebulon G., primary, Duveau, Damien Y., primary, Carelli, Ryan, primary, Singh, Reema, primary, Urbanucci, Alfonso, primary, Loda, Massimo, primary, Thomas, Craig J., primary, Mills, Ian G., primary, and Walker, Suzanne, primary

Published
2023
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34. Supplementary Figure 8 from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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35. Supplementary Figure 3 from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Braadland, Peder R., primary, Ramberg, Håkon, primary, Grytli, Helene Hartvedt, primary, Urbanucci, Alfonso, primary, Nielsen, Heidi Kristin, primary, Guldvik, Ingrid Jenny, primary, Engedal, Andreas, primary, Ketola, Kirsi, primary, Wang, Wanzhong, primary, Svindland, Aud, primary, Mills, Ian G., primary, Bjartell, Anders, primary, and Taskén, Kristin Austlid, primary

Published
2023
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36. ABI1 regulates transcriptional activity of Androgen Receptor by novel DNA and AR binding mechanism

Author

Baylee A. Porter, Xiang Li, Neeru Arya, Fan Zhang, Sonia H.Y. Kung, Ladan Fazli, Htoo Zarni Oo, Yinan Li, Kenneth Marincin, Konsta Kukkonen, Henna Urhonen, Maria A. Ortiz, Allysa P. Kemraj, Eva Corey, Xuesen Dong, Vladimir A. Kuznetsov, Matti Nykter, Martin E. Gleave, Gennady Bratslavsky, Alfonso Urbanucci, Dominique Frueh, Alaji Bah, and Leszek Kotula

Abstract

Transcription regulates key functions of living organisms in normal and disease states, including cell growth and development, embryonic and adult tissue organization, and tumor progression. Here we identify a novel mechanism of transcriptional regulation by an actin regulatory and signaling protein, Abelson Interactor 1 (ABI1). Using prostate cancer models, we uncover a reciprocal regulation between ABI1 and the Androgen Receptor (AR). ABI1 is a direct, androgen-regulated target; in turn, ABI1 interacts with AR and its splice variant ARv7, and co-regulates a subset of specific transcriptional targets. ABI1 directs transcription through transient yet well-defined interaction of its intrinsically disordered region with DNA. Clinical evaluation shows that the ABI1-DNA binding (through Exon 4 splicing) and ABI1-AR interaction are regulated during androgen deprivation therapy and prostate cancer progression, thus controlling tumor plasticity through connecting actin cytoskeleton and cellular signaling to transcriptional regulation. We propose ABI1 as epigenetic regulator of transcriptional homeostasis in AR-driven cancers.

Published
2023

38. Data from Inhibition of O-GlcNAc Transferase Renders Prostate Cancer Cells Dependent on CDK9

Author

Suzanne Walker, Ian G. Mills, Craig J. Thomas, Massimo Loda, Alfonso Urbanucci, Reema Singh, Ryan Carelli, Damien Y. Duveau, Zebulon G. Levine, Sara E.S. Martin, Rebecca E. Steele, Ninu Poulose, and Harri M. Itkonen

Abstract

O-GlcNAc transferase (OGT) is a nutrient-sensitive glycosyltransferase that is overexpressed in prostate cancer, the most common cancer in males. We recently developed a specific and potent inhibitor targeting this enzyme, and here, we report a synthetic lethality screen using this compound. Our screen identified pan-cyclin-dependent kinase (CDK) inhibitor AT7519 as lethal in combination with OGT inhibition. Follow-up chemical and genetic approaches identified CDK9 as the major target for synthetic lethality with OGT inhibition in prostate cancer cells. OGT expression is regulated through retention of the fourth intron in the gene and CDK9 inhibition blunted this regulatory mechanism. CDK9 phosphorylates carboxy-terminal domain (CTD) of RNA Polymerase II to promote transcription elongation. We show that OGT inhibition augments effects of CDK9 inhibitors on CTD phosphorylation and general transcription. Finally, the combined inhibition of both OGT and CDK9 blocked growth of organoids derived from patients with metastatic prostate cancer, but had minimal effects on normal prostate spheroids. We report a novel synthetic lethal interaction between inhibitors of OGT and CDK9 that specifically kills prostate cancer cells, but not normal cells. Our study highlights the potential of combining OGT inhibitors with other treatments to exploit cancer-specific vulnerabilities.Implications:The primary contribution of OGT to cell proliferation is unknown, and in this study, we used a compound screen to indicate that OGT and CDK9 collaborate to sustain a cancer cell–specific pro-proliferative program. A better understanding of how OGT and CDK9 cross-talk will refine our understanding of this novel synthetic lethal interaction.

Published
2023

39. Data from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Kristin Austlid Taskén, Anders Bjartell, Ian G. Mills, Aud Svindland, Wanzhong Wang, Kirsi Ketola, Andreas Engedal, Ingrid Jenny Guldvik, Heidi Kristin Nielsen, Alfonso Urbanucci, Helene Hartvedt Grytli, Håkon Ramberg, and Peder R. Braadland

Abstract

The incidence of treatment-related neuroendocrine prostate cancer (t-NEPC) is rising as more potent drugs targeting the androgen signaling axis are clinically implemented. Neuroendocrine transdifferentiation (NEtD), an putative initial step in t-NEPC development, is induced by androgen-deprivation therapy (ADT) or anti-androgens, and by activation of the β2-adrenergic receptor (ADRB2) in prostate cancer cell lines. Thus, understanding whether ADRB2 is involved in ADT-initiated NEtD may assist in developing treatment strategies that can prevent or reverse t-NEPC emergence, thereby prolonging therapeutic responses. Here we found that in primary, treatment-naïve prostate cancers, ADRB2 mRNA was positively correlated with expression of luminal differentiation markers, and ADRB2 protein levels were inversely correlated with Gleason grade. ADRB2 mRNA was upregulated in metastatic prostate cancer, and progressively downregulated during ADT and t-NEPC emergence. In androgen-deprivated medium, high ADRB2 was required for LNCaP cells to undergo NEtD, measured as increased neurite outgrowth and expression of neuron differentiation and neuroendocrine genes. ADRB2 overexpression induced a neuroendocrine-like morphology in both androgen receptor (AR)-positive and -negative prostate cancer cell lines. ADRB2 downregulation in LNCaP cells increased canonical Wnt signaling, and GSK3α/β inhibition reduced the expression of neuron differentiation and neuroendocrine genes. In LNCaP xenografts, more pronounced castration-induced NEtD was observed in tumors derived from high than low ADRB2 cells. In conclusion, high ADRB2 expression is required for ADT-induced NEtD, characterized by ADRB2 downregulation and t-NEPC emergence.Implications:This data suggest a potential application of β-blockers to prevent cancer cells committed to a neuroendocrine lineage from evolving into t-NEPC.

Published
2023

43. Supplementary Data from The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Author

Kristin Austlid Taskén, Anders Bjartell, Ian G. Mills, Aud Svindland, Wanzhong Wang, Kirsi Ketola, Andreas Engedal, Ingrid Jenny Guldvik, Heidi Kristin Nielsen, Alfonso Urbanucci, Helene Hartvedt Grytli, Håkon Ramberg, and Peder R. Braadland

Abstract

Supplementary Material and Methods, Supplementary Figure Legends, Supplementary Tables

Published
2023

45. Supplementary Data, Supplementary Figures and Legends 1-13 from Inhibition of O-GlcNAc Transferase Renders Prostate Cancer Cells Dependent on CDK9

Author

Suzanne Walker, Ian G. Mills, Craig J. Thomas, Massimo Loda, Alfonso Urbanucci, Reema Singh, Ryan Carelli, Damien Y. Duveau, Zebulon G. Levine, Sara E.S. Martin, Rebecca E. Steele, Ninu Poulose, and Harri M. Itkonen

Abstract

Supplementary figure 1. Validation of synthetic lethal interaction between OGT inhibition and AT7519 in LNCaP cells. Supplementary figure 2. Validation of synthetic lethal interaction between OSMI-2 and AT7519 in additional cell lines. Supplementary figure 3. Combination of OSMI-2 with AT7519 induces cells death in prostate cancer cells but not in cells derived from normal prostate epithelia. Supplementary figure 4. Characterization of RNA-seq data of cells treated with OGT inhibitor OSMI-2. Supplementary figure 5. OGT inhibition decreases phosphorylation of the carboxyterminal domain of RNA polymerase II. Supplementary figure 6. AT7519 enhances the effects of OGT inhibition by blocking the upregulation of OGT in PC3 cells. Supplementary figure 7. Summary of the RNA-seq data. Supplementary figure 8. Specific CDK9 inhibitor NVP2 is synthetically lethal in combination with OGT inhibition to LNCaP prostate cancer cells. Supplementary figure 9. OGT inhibition potentiates the anti-proliferative effects of CDK9 inhibitors Dinaciclib and SB1317 on prostate cancer cells. Supplementary figure 10. Knockdown of CDK9 sensitizes LNCaP prostate cancer cells to OGT inhibition. Supplementary figure 11. Combination of OSMI-2 with AT7519 further decreases the mRNA abundance of most mRNAs with half-life less than 4 hours. Supplementary figure 12. Determination of CDK9 inhibitor dose suitable for organoid experiments. Supplementary figure 13. Validation of synthetic lethality between inhibitors of OGT and CDK9 using models of castration-resistant prostate cancer (CRPC).

Published
2023

49. Enhancer profiling identifies epigenetic markers of endocrine resistance and reveals therapeutic options for metastatic castration-resistant prostate cancer patients

Author

Severson, Tesa M., primary, Zhu, Yanyun, additional, Prekovic, Stefan, additional, Schuurman, Karianne, additional, Nguyen, Holly M., additional, Brown, Lisha G., additional, Hakkola, Sini, additional, Kim, Yongsoo, additional, Kneppers, Jeroen, additional, Linder, Simon, additional, Stelloo, Suzan, additional, Lieftink, Cor, additional, van der Heijden, Michiel, additional, Nykter, Matti, additional, van der Noort, Vincent, additional, Sanders, Joyce, additional, Morris, Ben, additional, Jenster, Guido, additional, van Leenders, Geert JLH, additional, Pomerantz, Mark, additional, Freedman, Matthew L., additional, Beijersbergen, Roderick L., additional, Urbanucci, Alfonso, additional, Wessels, Lodewyk, additional, Corey, Eva, additional, Zwart, Wilbert, additional, and Bergman, Andries M., additional

Published
2023
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50. Clinical testing of transcriptome-wide expression profiles in high-risk localized and metastatic prostate cancer starting androgen deprivation therapy: an ancillary study of the STAMPEDE abiraterone Phase 3 trial

Author

Attard, Gerhardt, primary, Parry, Marina, additional, Grist, Emily, additional, Mendes, Larissa, additional, Dutey-Magni, Peter, additional, Sachdeva, Ashwin, additional, Brawley, Christopher, additional, Murphy, Laura, additional, Proudfoot, James, additional, Lall, Sharanpreet, additional, Liu, Yang, additional, Friedrich, Stefanie, additional, Ismail, Mazlina, additional, Hoyle, Alex, additional, Ali, Adnan, additional, Haran, Aine, additional, Wingate, Anna, additional, Zakka, Leila, additional, Wetterskog, Daniel, additional, Amos, Claire, additional, Atako, Nafisah, additional, Wang, Victoria, additional, Rush, Hannah, additional, Jones, Robert, additional, Leung, Hing, additional, Cross, William, additional, gillessen, silke, additional, Parker, Chris, additional, Chowdhury, Simon, additional, Lotan, Tamara, additional, Marafioti, Teresa, additional, Urbanucci, Alfonso, additional, Schaeffer, Edward, additional, Spratt, Daniel, additional, Waugh, David, additional, Powles, Thomas, additional, Berney, Daniel, additional, Sydes, Matthew, additional, Parmar, Mahesh, additional, Hamid, Anis, additional, Feng, Felix, additional, Sweeney, Christopher, additional, Davicioni, Elai, additional, Clarke, Noel, additional, James, Nicholas, additional, and Brown, Louise, additional

Published
2023
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