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Jernberg, Emma
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Publications (10 of 21) Show all publications
Thysell, E., Vidman, L., Bovinder Ylitalo, E., Jernberg, E., Crnalic, S., Iglesias-Gato, D., . . . Wikström, P. (2019). Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor. Molecular Oncology, 13(8), 1763-1777
Open this publication in new window or tab >>Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor
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2019 (English)In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 13, no 8, p. 1763-1777Article in journal (Refereed) Published
Abstract [en]

Bone metastasis is the lethal end-stage of prostate cancer (PC), but the biology of bone metastases is poorly understood. The overall aim of this study was therefore to explore molecular variability in PC bone metastases of potential importance for therapy. Specifically, genome-wide expression profiles of bone metastases from untreated patients (n = 12) and patients treated with androgen-deprivation therapy (ADT, n = 60) were analyzed in relation to patient outcome and to morphological characteristics in metastases and paired primary tumors. Principal component analysis and unsupervised classification were used to identify sample clusters based on mRNA profiles. Clusters were characterized by gene set enrichment analysis and related to histological and clinical parameters using univariate and multivariate statistics. Selected proteins were analyzed by immunohistochemistry in metastases and matched primary tumors (n = 52) and in transurethral resected prostate (TUR-P) tissue of a separate cohort (n = 59). Three molecular subtypes of bone metastases (MetA-C) characterized by differences in gene expression pattern, morphology, and clinical behavior were identified. MetA (71% of the cases) showed increased expression of androgen receptor-regulated genes, including prostate-specific antigen (PSA), and glandular structures indicating a luminal cell phenotype. MetB (17%) showed expression profiles related to cell cycle activity and DNA damage, and a pronounced cellular atypia. MetC (12%) exhibited enriched stroma-epithelial cell interactions. MetB patients had the lowest serum PSA levels and the poorest prognosis after ADT. Combined analysis of PSA and Ki67 immunoreactivity (proliferation) in bone metastases, paired primary tumors, and TUR-P samples was able to differentiate MetA-like (high PSA, low Ki67) from MetB-like (low PSA, high Ki67) tumors and demonstrate their different prognosis. In conclusion, bone metastases from PC patients are separated based on gene expression profiles into molecular subtypes with different morphology, biology, and clinical outcome. These findings deserve further exploration with the purpose of improving treatment of metastatic PC.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
bone metastasis, gene expression, gene set enrichment analysis, morphology, survival, unsupervised cluster analysis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-162668 (URN)10.1002/1878-0261.12526 (DOI)000478600200009 ()31162796 (PubMedID)
Available from: 2019-09-05 Created: 2019-09-05 Last updated: 2019-09-05Bibliographically approved
Nordstrand, A., Bovinder Ylitalo, E., Thysell, E., Jernberg, E., Crnalic, S., Widmark, A., . . . Wikström, P. (2018). Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity. International Journal of Molecular Sciences, 19(4), Article ID 1223.
Open this publication in new window or tab >>Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity
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2018 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, no 4, article id 1223Article in journal (Refereed) Published
Abstract [en]

Advanced prostate cancer frequently metastasizes to bone and induces a mixed osteoblastic/osteolytic bone response. Standard treatment for metastatic prostate cancer is androgen-deprivation therapy (ADT) that also affects bone biology. Treatment options for patients relapsing after ADT are limited, particularly in cases where castration-resistance does not depend on androgen receptor (AR) activity. Patients with non-AR driven metastases may, however, benefit from therapies targeting the tumor microenvironment. Therefore, the current study specifically investigated bone cell activity in clinical bone metastases in relation to tumor cell AR activity, in order to gain novel insight into biological heterogeneities of possible importance for patient stratification into bone-targeting therapies. Metastasis tissue obtained from treatment-naïve (n = 11) and castration-resistant (n = 28) patients was characterized using whole-genome expression analysis followed by multivariate modeling, functional enrichment analysis, and histological evaluation. Bone cell activity was analyzed by measuring expression levels of predefined marker genes representing osteoclasts (ACP5, CTSK, MMP9), osteoblasts (ALPL, BGLAP, RUNX2) and osteocytes (SOST). Principal component analysis indicated a positive correlation between osteoblast and osteoclast activity and a high variability in bone cell activity between different metastases. Immunohistochemistry verified a positive correlation between runt-related transcription factor 2 (RUNX2) positive osteoblasts and tartrate-resistant acid phosphatase (TRAP, encoded by ACP5) positive osteoclasts lining the metastatic bone surface. No difference in bone cell activity was seen between treatment-naïve and castration-resistant patients. Importantly, bone cell activity was inversely correlated to tumor cell AR activity (measured as AR, FOXA1, HOXB13, KLK2, KLK3, NKX3-1, STEAP2, and TMPRSS2 expression) and to patient serum prostate-specific antigen (PSA) levels. Functional enrichment analysis indicated high bone morphogenetic protein (BMP) signaling in metastases with high bone cell activity and low tumor cell AR activity. This was confirmed by BMP4 immunoreactivity in tumor cells of metastases with ongoing bone formation, as determined by histological evaluation of van Gieson-stained sections. In conclusion, the inverse relation observed between bone cell activity and tumor cell AR activity in prostate cancer bone metastasis may be of importance for patient response to AR and/or bone targeting therapies, but needs to be evaluated in clinical settings in relation to serum markers for bone remodeling, radiography and patient response to therapy. The importance of BMP signaling in the development of sclerotic metastasis lesions deserves further exploration.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
prostate cancer, bone, metastasis, androgen receptor, osteoblast, osteoclast, BMP
National Category
Orthopaedics
Identifiers
urn:nbn:se:umu:diva-146973 (URN)10.3390/ijms19041223 (DOI)000434978700302 ()29670000 (PubMedID)2-s2.0-85045938451 (Scopus ID)
Available from: 2018-04-24 Created: 2018-04-24 Last updated: 2018-11-21Bibliographically approved
Bovinder Ylitalo, E., Nordstrand, A., Thysell, E., Jernberg, E., Crnalic, S., Widmark, A., . . . Wikström, P. (2018). Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases. Paper presented at AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL. Cancer Research, 78(16), 50-50
Open this publication in new window or tab >>Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases
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2018 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 16, p. 50-50Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
American Association for Cancer Research, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-151399 (URN)000441803800065 ()
Conference
AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL
Note

Supplement: S, Meeting Abstract: A048

Available from: 2018-09-05 Created: 2018-09-05 Last updated: 2018-09-05Bibliographically approved
Thysell, E., Bovinder Ylitalo, E., Jernberg, E., Crnalic, S., Widmark, A., Bergh, A. & Wikström, P. (2018). Clinically relevant molecular subgroups of prostate cancer bone metastases. Paper presented at AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL. Cancer Research, 78(16), 123-123
Open this publication in new window or tab >>Clinically relevant molecular subgroups of prostate cancer bone metastases
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2018 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 16, p. 123-123Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
American Association for Cancer Research, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-151398 (URN)000441803800194 ()
Conference
AACR Special Conference on Prostate Cancer - Advances in Basic, Translational, and Clinical Research, DEC 02-05, 2017, Orlando, FL
Note

 Supplement: S, Meeting Abstract: B081

Available from: 2018-09-05 Created: 2018-09-05 Last updated: 2018-09-05Bibliographically approved
Thysell, E., Bovinder Ylitalo, E., Jernberg, E., Bergh, A. & Wikström, P. (2017). A Systems Approach to Prostate Cancer Classification: Letter [Letter to the editor]. Cancer Research, 77(24), 7131-7132
Open this publication in new window or tab >>A Systems Approach to Prostate Cancer Classification: Letter
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2017 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 24, p. 7131-7132Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
American Association for Cancer Research, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-143503 (URN)10.1158/0008-5472.CAN-16-3231 (DOI)000418189800029 ()29212852 (PubMedID)
Available from: 2018-01-03 Created: 2018-01-03 Last updated: 2018-06-09Bibliographically approved
Jernberg, E., Bergh, A. & Wikström, P. (2017). Clinical relevance of androgen receptor alterations in prostate cancer. Endocrine Connections, 6(8), R146-R161
Open this publication in new window or tab >>Clinical relevance of androgen receptor alterations in prostate cancer
2017 (English)In: Endocrine Connections, ISSN 2049-3614, E-ISSN 2049-3614, Vol. 6, no 8, p. R146-R161Article, review/survey (Refereed) Published
Abstract [en]

Prostate cancer (PC) remains a leading cause of cancer-related deaths among men worldwide, despite continuously improved treatment strategies. Patients with metastatic disease are treated by androgen deprivation therapy (ADT) that with time results in the development of castration-resistant prostate cancer (CRPC) usually established as metastases within bone tissue. The androgen receptor (AR) transcription factor is the main driver of CRPC development and of acquired resistance to drugs given for treatment of CRPC, while a minority of patients have CRPC that is non-AR driven. Molecular mechanisms behind epithelial AR reactivation in CRPC include AR gene amplification and overexpression, AR mutations, expression of constitutively active AR variants, intra-tumoural and adrenal androgen synthesis and promiscuous AR activation by other factors. This review will summarize AR alterations of clinical relevance for patients with CRPC, with focus on constitutively active AR variants, their possible association with AR amplification and structural rearrangements as well as their ability to predict patient resistance to AR targeting drugs. The review will also discuss AR signalling in the tumour microenvironment and its possible relevance for metastatic growth and therapy.

Keywords
prostate cancer, castration resistance, androgen receptor
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-144124 (URN)10.1530/EC-17-0118 (DOI)000418497500001 ()29030409 (PubMedID)
Funder
Swedish Research Council, K2013-64X-20407-04-3Swedish Cancer Society, CAN 2016/824Swedish Cancer Society, CAN 2013/1324
Available from: 2018-01-23 Created: 2018-01-23 Last updated: 2019-05-10Bibliographically approved
Djusberg, E., Jernberg, E., Thysell, E., Golovleva, I., Lundberg, P., Crnalic, S., . . . Wikström, P. (2017). High Levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases. The Prostate, 77(6), 625-638
Open this publication in new window or tab >>High Levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases
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2017 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 77, no 6, p. 625-638Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. METHODS: Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis. Whole genome mRNA expression was analyzed using H12 Illumina Beadchip arrays and specific transcript levels were quantified by qRT-PCR. Protein localization was analyzed using immunohistochemistry and confocal microscopy. The YIPF6 mRNA expression was transiently knocked down and stably overexpressed in the 22Rv1 cell line as representative for CRPC, and effects on cell proliferation, colony formation, migration, and invasion were determined in vitro. Extracellular vesicles (EVs) were isolated from cell cultures using size-exclusion chromatography and enumerated by nanoparticle tracking analysis. Protein content was identified by LC-MS/MS analysis. Blood coagulation was measured as activated partial thromboplastin time (APTT). Functional enrichment analysis was performed using the MetaCore software. RESULTS: AR amplification was detected in 16 (53%) of the bone metastases examined from CRPC patients (n = 30), and in none from the untreated patients (n = 10). Metastases with AR amplification showed high AR and AR-V7 mRNA levels, increased nuclear AR immunostaining, and co-amplification of genes such as YIPF6 in the AR proximity at Xq12. The YIPF6 protein was localized to the Golgi apparatus. YIPF6 overexpression in 22Rv1 cells resulted in reduced cell proliferation and colony formation, and in enhanced EV secretion. EVs from YIPF6 overproducing 22Rv1 cells were enriched for proteins involved in blood coagulation and, accordingly, decreased the APTT in a dose-dependent fashion. CONCLUSIONS: AR amplified CRPC bone metastases show high AR-V7 expression that probably gives resistance to AR-targeting drugs. Co-amplification of the Golgi protein coding YIPF6 gene with the AR may enhance the secretion of pro-coagulative EVs from cancer cells and thereby stimulate tumor progression and increase the coagulopathy risk in CRPC patients.

Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2017
Keywords
androgen receptor variant 7, AKR1C3, extracellular vesicles, exosomes, blood coagulation
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-131817 (URN)10.1002/pros.23307 (DOI)000397496300007 ()28144969 (PubMedID)
Available from: 2017-02-22 Created: 2017-02-22 Last updated: 2018-06-09Bibliographically approved
Thysell, E., Ylitalo, E. B., Jernberg, E., Bergh, A. & Wikström, P. (2017). Reply to Isabel Heidegger, Renate Pichler, and Andreas Pircher's Letter to the Editor re: Erik Bovinder Ylitalo, Elin Thysell, Emma Jernberg, et al. Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response. Eur Urol 2017;71:776-87 [Letter to the editor]. European Urology, 72(4), e104-e105
Open this publication in new window or tab >>Reply to Isabel Heidegger, Renate Pichler, and Andreas Pircher's Letter to the Editor re: Erik Bovinder Ylitalo, Elin Thysell, Emma Jernberg, et al. Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response. Eur Urol 2017;71:776-87
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2017 (English)In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 72, no 4, p. e104-e105Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-140032 (URN)10.1016/j.eururo.2017.06.009 (DOI)000410389900008 ()28642023 (PubMedID)
Available from: 2018-01-04 Created: 2018-01-04 Last updated: 2018-06-09Bibliographically approved
Thysell, E., Ylitalo, E. B., Jernberg, E., Bergh, A. & Wikström, P. (2017). Reply to Isabel Heidegger, Renate Pichler, and Andreas Pircher's Letter to the Editor re: Erik Bovinder Ylitalo, Elin Thysell, Emma Jernberg, et al. Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response. Eur Urol 2017;71:776-87 [Letter to the editor]. European Urology, 72(4), E104-E105
Open this publication in new window or tab >>Reply to Isabel Heidegger, Renate Pichler, and Andreas Pircher's Letter to the Editor re: Erik Bovinder Ylitalo, Elin Thysell, Emma Jernberg, et al. Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response. Eur Urol 2017;71:776-87
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2017 (English)In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 72, no 4, p. E104-E105Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
Elsevier, 2017
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-142919 (URN)10.1016/j.eururo.2017.06.009 (DOI)000410389900008 ()28642023 (PubMedID)
Available from: 2017-12-13 Created: 2017-12-13 Last updated: 2018-06-09Bibliographically approved
Bovinder Ylitalo, E., Thysell, E., Jernberg, E., Lundholm, M., Crnalic, S., Egevad, L., . . . Wikström, P. (2017). Subgroups of castration-resistant prostate cancer bone metastases defined through an inverse relationship between androgen receptor activity and immune response. European Urology, 71(5), 776-787
Open this publication in new window or tab >>Subgroups of castration-resistant prostate cancer bone metastases defined through an inverse relationship between androgen receptor activity and immune response
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2017 (English)In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 71, no 5, p. 776-787Article in journal (Refereed) Published
Abstract [en]

Background: Novel therapies for men with castration-resistant prostate cancer (CRPC) are needed, particularly for cancers not driven by androgen receptor (AR) activation. Objectives: To identify molecular subgroups of PC bone metastases of relevance for therapy.

Design, setting, and participants: Fresh-frozen bone metastasis samples from men with CRPC (n = 40), treatment-naïve PC (n = 8), or other malignancies (n = 12) were characterized using whole-genome expression profiling, multivariate principal component analysis (PCA), and functional enrichment analysis. Expression profiles were verified by reverse transcription–polymerase chain reaction (RT-PCR) in an extended set of bone metastases (n = 77) and compared to levels in malignant and adjacent benign prostate tissue from patients with localized disease (n = 12). Selected proteins were evaluated using immunohistochemistry. A cohort of PC patients (n = 284) diagnosed at transurethral resection with long follow-up was used for prognostic evaluation.

Results and limitations: The majority of CRPC bone metastases (80%) was defined as AR-driven based on PCA analysis and high expression of the AR, AR co-regulators (FOXA1, HOXB13), and AR-regulated genes (KLK2, KLK3, NKX3.1, STEAP2, TMPRSS2); 20% were non–AR-driven. Functional enrichment analysis indicated high metabolic activity and low immune responses in AR-driven metastases. Accordingly, infiltration of CD3+ and CD68+ cells was lower in AR-driven than in non–AR-driven metastases, and tumor cell HLA class I ABC immunoreactivity was inversely correlated with nuclear AR immunoreactivity. RT-PCR analysis showed low MHC class I expression (HLA-A, TAP1, and PSMB9 mRNA) in PC bone metastases compared to benign and malignant prostate tissue and bone metastases of other origins. In primary PC, low HLA class I ABC immunoreactivity was associated with high Gleason score, bone metastasis, and short cancer-specific survival. Limitations include the limited number of patients studied and the single metastasis sample studied per patient.

Conclusions: Most CRPC bone metastases show high AR and metabolic activities and low immune responses. A subgroup instead shows low AR and metabolic activities, but high immune responses. Targeted therapy for these groups should be explored. Patient summary: We studied heterogeneities at a molecular level in bone metastasis samples obtained from men with castration-resistant prostate cancer. We found differences of possible importance for therapy selection in individual patients.

Keywords
Bone metastasis, Castration-resistance, Immune response, Metabolism, Prostate cancer
National Category
Cancer and Oncology Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-131852 (URN)10.1016/j.eururo.2016.07.033 (DOI)000397773300033 ()27497761 (PubMedID)
Available from: 2017-02-23 Created: 2017-02-23 Last updated: 2019-05-17Bibliographically approved
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