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- Berglund, Emelie, et al.
(författare)
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Spatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Intra-tumor heterogeneity is one of the biggest challenges in cancer treatment today. Here we investigate tissue-wide gene expression heterogeneity throughout a multifocal prostate cancer using the spatial transcriptomics (ST) technology. Utilizing a novel approach for deconvolution, we analyze the transcriptomes of nearly 6750 tissue regions and extract distinct expression profiles for the different tissue components, such as stroma, normal and PIN glands, immune cells and cancer. We distinguish healthy and diseased areas and thereby provide insight into gene expression changes during the progression of prostate cancer. Compared to pathologist annotations, we delineate the extent of cancer foci more accurately, interestingly without link to histological changes. We identify gene expression gradients in stroma adjacent to tumor regions that allow for re-stratification of the tumor microenvironment. The establishment of these profiles is the first step towards an unbiased view of prostate cancer and can serve as a dictionary for future studies.
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| 3. |
- Erlandsson, Ann, 1968-, et al.
(författare)
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Infiltrating immune cells in prostate cancer tissue after androgen deprivation and radiotherapy
- 2023
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Ingår i: International journal of immunopathology and pharmacology. - : Sage Publications. - 0394-6320 .- 2058-7384. ; 37
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Androgen deprivation therapy (ADT) has long been a cornerstone in treatment of advanced prostate cancer (PCa), and is known to improve the results of radiotherapy (RT) for high-risk disease. The purpose of our study was to use a multiplexed immunohistochemical (mIHC) approach to investigate the infiltration of immune cells in PCa tissue after eight weeks of ADT and/or RT with 10 Gy.Methods: From a cohort of 48 patients divided into two treatment arms, we obtained biopsies before and after treatment and used a mIHC method with multispectral imaging to analyze the infiltration of immune cells in tumor stroma and tumor epithelium, focusing on areas with high infiltration.Results: Tumor stroma showed a significantly higher infiltration of immune cells compared to tumor epithelium. The most prominent immune cells were CD20(+) B-lymphocytes, followed by CD68(+) macrophages, CD8(+) cytotoxic T-cells, FOXP3(+) regulatory T-cells (Tregs), and T-bet(+) Th1-cells. Neoadjuvant ADT followed by RT significantly increased the infiltration of all five immune cells. Numbers of Th1-cells and Tregs significantly increased after single treatment with ADT or RT. In addition, ADT alone increased the number of cytotoxic T-cells and RT increased the number of B-cells.Conclusions: Neoadjuvant ADT in combination with RT results in a higher inflammatory response compared to RT or ADT alone. The mIHC method may be a useful tool for investigating infiltrating immune cells in PCa biopsies to understand how immunotherapeutic approaches can be combined with current PCa therapies.
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| 4. |
- Marklund, Maja, et al.
(författare)
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Spatio-temporal analysis of prostate tumors in situ suggests pre-existence of treatment-resistant clones
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- The molecular mechanisms underlying lethal castration-resistant prostate cancer remain poorly understood, with intratumoral heterogeneity a likely contributing factor. To examine the temporal aspects of resistance, we analyze tumor heterogeneity in needle biopsies collected before and after treatment with androgen deprivation therapy. By doing so, we are able to couple clinical responsiveness and morphological information such as Gleason score to transcriptome-wide data. Our data-driven analysis of transcriptomes identifies several distinct intratumoral cell populations, characterized by their unique gene expression profiles. Certain cell populations present before treatment exhibit gene expression profiles that match those of resistant tumor cell clusters, present after treatment. We confirm that these clusters are resistant by the localization of active androgen receptors to the nuclei in cancer cells post-treatment. Our data also demonstrates that most stromal cells adjacent to resistant clusters do not express the androgen receptor, and we identify differentially expressed genes for these cells. Altogether, this study shows the potential to increase the power in predicting resistant tumors. Spatial heterogeneity in prostate cancer can contribute to its resistance to androgen deprivation therapy (ADT). Here, the authors analyse prostate cancer samples before and after ADT using Spatial Transcriptomics, and find heterogeneous pre-treatment tumour cell populations and stromal cells that are associated with resistance.
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| 5. |
- Marklund, Maja, et al.
(författare)
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Spatio-temporal analysis of prostate tumors in situ suggests the pre-existence of ADT-resistance
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The molecular mechanisms by which potentially lethal castration-resistant prostate cancer emerge in advanced metastatic prostate cancer are still poorly understood. Intratumor heterogeneity is believed to contribute to the fact that a majority of affected men succumb to the disease within a few years. In this study, we will challenge the conventional notion that castration-resistant prostate cancer cells evolve as a consequence of treatment. To examine the temporal aspects of resistance, we analyze tumor heterogeneity in core needle biopsies collected pre-and post-treatment. By doing so, we are able to couple clinical responsiveness and morphological information such as Gleason score to transcriptome- wide data. Our data-driven analysis of transcriptomes identified several distinct intratumoral cell populations, characterized by their unique gene expression profiles. Strikingly, certain minor cell populations present before treatment exhibited gene expression profiles that matched those of resistant tumor cell clusters. Such resistant clusters were confirmed by the localization of the androgen receptor to the nuclei in cancer cells present after treatment. Our data also demonstrate that stromal cells adjacent to resistant tumor factors do not express AR before treatment (or after), which can be used to increase the power in predicting resistant tumors.
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| 7. |
- Tarish, Firas L., et al.
(författare)
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Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand break repair
- 2015
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 7:312
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Tidskriftsartikel (refereegranskat)abstract
- Chemical castration improves responses to radiotherapy in prostate cancer, but the mechanism is unknown. We hypothesized that this radiosensitization is caused by castration-mediated down-regulation of non-homologous end joining (NHEJ) repair of DNA double-strand breaks (DSBs). To test this, we enrolled 48 patients with localized prostate cancer in two arms of the study: either radiotherapy first or radiotherapy after neoadjuvant castration treatment. We biopsied patients at diagnosis and before and after castration and radiotherapy treatments to monitor androgen receptor, NHEJ, and DSB repair in verified cancer tissue. We show that patients receiving neoadjuvant castration treatment before radiotherapy had reduced amounts of the NHEJ protein Ku70, impaired radiotherapy-induced NHEJ activity, and higher amounts of unrepaired DSBs, measured by gamma-H2AX foci in cancer tissues. This study demonstrates that chemical castration impairs NHEJ activity in prostate cancer tissue, explaining the improved response of patients with prostate cancer to radiotherapy after chemical castration.
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| 8. |
- Tarish, Firas L
(författare)
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Study of the mechanisms behind the additive effect of neoadjuvant castration on radiotherapy for prostate cancer
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Castration improves responses to radiotherapy (RT) in prostate cancer with unknown mechanism. An understanding of what happens at the cellular and molecular level in prostate cancer cells, while reducing their access to androgens and then exposing them to ionizing radiation (IR), would give us an opportunity to optimize the treatment and may also inspire novel therapeutic approaches. Paper I: Growth of solid tumours such as prostate cancer is characterized by neovascularization and increased glycolysis as a result of the hypoxic microenvironment of the tumour. HIF-1α is an important transcription factor that regulates cell adaptation to hypoxia and transcription of genes involved in angiogenesis, cell survival, glucose metabolism, and tumour invasion. To test whether any connection between castration therapy and intra-tumoural hypoxia, measured by HIF-1α expression, prostate biopsy specimens from 14 patients with prostate cancer were investigated. Downregulation of HIF-1α expression after castration was observed in five patients with initial high HIF-1α expression. HIF-1α expression was also reduced in two of three patients with initial low HIF-1α expression. These data suggest that neoadjuvant castration reduces tumour cell hypoxia in prostate cancer, which may contribute to the increased radiosensitivity after castration. Paper II: We investigated whether castration impairs non-homologous end-joining (NHEJ) repair of DNA double-strand breaks (DSBs) by downregulation of Ku70 expression. The same cohort of patients used in paper I was analysed. After castration, the nuclear Ku70 levels were reduced in 12 patients (levels varied from 43% to 97% after castration, p <0.001). The reduction in Ku70 expression correlated significantly with the decrease of serum PSA level after castration, suggesting that AR activity regulates Ku70 protein levels in prostate cancer tissue. Our conclusion was that castration results in decreased levels of Ku70 protein. Since Ku70 protein is necessary for NHEJ repair of DSBs, a downregulation of DNA repair leads to increased radiosensitivity. Paper III: Emerging data demonstrate homologous recombination (HR) defects in castration resistant malignant prostate tumours, rendering these sensitive to PARP inhibitor treatments. Here, we demonstrate a direct link between the androgen receptor (AR) being required for maintenance of HR gene expression and activity in prostate cancer cells, as well as in maintenance of DNA damage response signalling. As a consequence, we show PARP-mediated backup repair pathway is upregulated in prostate cancer tissues in patients following androgen-deprivation therapy (ADT). Furthermore, upregulation of PARP activity is essential for prostate cancer survival, and we demonstrate a synthetic lethality between ADT and PARP inhibitors in vivo. These data demonstrate that HR may be functionally impaired earlier in prostate cancer etiology as a consequence of ADT; prior to emerging castration resistance and that this potentially can be exploited therapeutically using PARP inhibitors in combination with an ADT upfront in advanced or high risk prostate cancer. Paper IV: Since castration improves responses to radiotherapy (RT) in prostate cancer, we hypothesized that this radiosensitization is caused by castration-mediated down-regulation of non homologous end joining (NHEJ) repair of DNA double-strand breaks (DSBs). To test this, forty-eight patients with localized prostate cancer were enrolled in two arms, either treating with RT upfront or after receiving neo-adjuvant castration. We biopsied patients at diagnosis, before and after castration and RT treatments to monitor androgen receptor (AR), NHEJ and DSB repair in verified cancer tissue. We show that patients receiving neoadjuvant castration prior to RT had reduced levels of the NHEJ protein Ku70, impaired RTinduced NHEJ activity and a higher level of unrepaired DSBs, measured by γ-H2AX foci in cancer tissues. This study demonstrates that castration impairs NHEJ activity in prostate cancer tissue, explaining improved RT responses in tumours. Paper V: Despite the early diagnosis and subsequently effective treatment of intermediate and high-risk prostate cancer, the recurrence rate remains regrettably high. Here, we wanted to investigate how effectively castration suppresses androgen receptor (AR) signalling, thereby affecting DNA damage repair in primary hormone-naïve prostate cancer. From the same cohort of patients as in Paper IV, four patients from arm 1 and one patient from arm 2 were analysed. The levels of AR, Ku70, phosphorylated DNA-PKcs and PAR were measured. A significant correlated reduction in the mean intensity of nuclear AR was observed in four patients whose serum PSA was reduced to the greatest extent, about 90% (ρ=1, p <0.001). Although complete castration was obtained using serum testosterone levels in these patients, the levels of AR, and consequently of Ku70 and phosphorylated DNAPKcs remained high and positively co-varied in clusters of cells throughout prostate tumour areas. Meanwhile, a tendency towards an inverse correlation was observed between AR, Ku70 and phosphorylated DNA-PKcs as compared with PARP-1 activity. In conclusion, we are first to demonstrate the heterogeneous landscape of AR and the consequent divergent although co-varied response of DNA damage repair. To date, it remains unclear whether the emergence of these castration-resistant cells in hormone-naïve prostate cancer, is due to the high levels of intra-tumoural residual androgen following castration and consequently suboptimal androgen suppression of otherwise androgen-dependent cells or caused by quiescent castration-resistant cells that promote progression according to clonal selection pressure. The current finding certainly warrants further investigation in the future.
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