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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.

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.

Understanding the heterogeneous molecular landscape of prostate cancer is fundamental to improve treatment of the disease. Here, we aim to provide a broad molecular view of a cross- section of a prostate organ. This study manifests several unique tumor gene expression subtypes, with adjacent stroma, occupying distinct and different anatomical regions. The interplay between multiple molecularly defined tumor gene expression factors and/or Gleason scoring and the corresponding tumor microenvironment was hereby studied in detail. We perform a molecular sub-categorization of the tumor microenvironment throughout the whole prostate, using three different molecular principles; (i) AR staining, since loss of stromal AR is directly proportional to the degree of differentiation (Gleason score), (ii) Masson staining for its role in marking reactive stroma, and (iii) spatial transcriptomics analysis. In particular, we performed a detailed analysis of spatial distribution in histologic sections at the invasive border of a tumor foci contrasting it to the tumor core. Here, we show spatially confined DEPDC1, CHN1 and CRISP3 upregulation at the invasive border with implications of signal transduction pathways such as; PTEN, TGF-beta Receptor Complex, NOTCH4, ERBB2, and VEGF signaling, some of which are druggable. Overall, our results show an unprecedented view of the molecular heterogeneity of a prostate cancer not evident by other means. Here, we reveal patient-specific gene expression hallmarks from low to aggressive cancer within the same cross section of a prostate.

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., QC 20200511

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., QC 20200511

Understanding the heterogeneous molecular landscape of prostate cancer is fundamental to improve treatment of the disease. Here, we aim to provide a broad molecular view of a cross- section of a prostate organ. This study manifests several unique tumor gene expression subtypes, with adjacent stroma, occupying distinct and different anatomical regions. The interplay between multiple molecularly defined tumor gene expression factors and/or Gleason scoring and the corresponding tumor microenvironment was hereby studied in detail. We perform a molecular sub-categorization of the tumor microenvironment throughout the whole prostate, using three different molecular principles; (i) AR staining, since loss of stromal AR is directly proportional to the degree of differentiation (Gleason score), (ii) Masson staining for its role in marking reactive stroma, and (iii) spatial transcriptomics analysis. In particular, we performed a detailed analysis of spatial distribution in histologic sections at the invasive border of a tumor foci contrasting it to the tumor core. Here, we show spatially confined DEPDC1, CHN1 and CRISP3 upregulation at the invasive border with implications of signal transduction pathways such as; PTEN, TGF-beta Receptor Complex, NOTCH4, ERBB2, and VEGF signaling, some of which are druggable. Overall, our results show an unprecedented view of the molecular heterogeneity of a prostate cancer not evident by other means. Here, we reveal patient-specific gene expression hallmarks from low to aggressive cancer within the same cross section of a prostate.

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., QC 20200511

Understanding the heterogeneous molecular landscape of prostate cancer is fundamental to improve treatment of the disease. Here, we aim to provide a broad molecular view of a cross- section of a prostate organ. This study manifests several unique tumor gene expression subtypes, with adjacent stroma, occupying distinct and different anatomical regions. The interplay between multiple molecularly defined tumor gene expression factors and/or Gleason scoring and the corresponding tumor microenvironment was hereby studied in detail. We perform a molecular sub-categorization of the tumor microenvironment throughout the whole prostate, using three different molecular principles; (i) AR staining, since loss of stromal AR is directly proportional to the degree of differentiation (Gleason score), (ii) Masson staining for its role in marking reactive stroma, and (iii) spatial transcriptomics analysis. In particular, we performed a detailed analysis of spatial distribution in histologic sections at the invasive border of a tumor foci contrasting it to the tumor core. Here, we show spatially confined DEPDC1, CHN1 and CRISP3 upregulation at the invasive border with implications of signal transduction pathways such as; PTEN, TGF-beta Receptor Complex, NOTCH4, ERBB2, and VEGF signaling, some of which are druggable. Overall, our results show an unprecedented view of the molecular heterogeneity of a prostate cancer not evident by other means. Here, we reveal patient-specific gene expression hallmarks from low to aggressive cancer within the same cross section of a prostate.

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., QC 20200511

Understanding the heterogeneous molecular landscape of prostate cancer is fundamental to improve treatment of the disease. Here, we aim to provide a broad molecular view of a cross- section of a prostate organ. This study manifests several unique tumor gene expression subtypes, with adjacent stroma, occupying distinct and different anatomical regions. The interplay between multiple molecularly defined tumor gene expression factors and/or Gleason scoring and the corresponding tumor microenvironment was hereby studied in detail. We perform a molecular sub-categorization of the tumor microenvironment throughout the whole prostate, using three different molecular principles; (i) AR staining, since loss of stromal AR is directly proportional to the degree of differentiation (Gleason score), (ii) Masson staining for its role in marking reactive stroma, and (iii) spatial transcriptomics analysis. In particular, we performed a detailed analysis of spatial distribution in histologic sections at the invasive border of a tumor foci contrasting it to the tumor core. Here, we show spatially confined DEPDC1, CHN1 and CRISP3 upregulation at the invasive border with implications of signal transduction pathways such as; PTEN, TGF-beta Receptor Complex, NOTCH4, ERBB2, and VEGF signaling, some of which are druggable. Overall, our results show an unprecedented view of the molecular heterogeneity of a prostate cancer not evident by other means. Here, we reveal patient-specific gene expression hallmarks from low to aggressive cancer within the same cross section of a prostate.

Understanding the heterogeneous molecular landscape of prostate cancer is fundamental to improve treatment of the disease. Here, we aim to provide a broad molecular view of a cross- section of a prostate organ. This study manifests several unique tumor gene expression subtypes, with adjacent stroma, occupying distinct and different anatomical regions. The interplay between multiple molecularly defined tumor gene expression factors and/or Gleason scoring and the corresponding tumor microenvironment was hereby studied in detail. We perform a molecular sub-categorization of the tumor microenvironment throughout the whole prostate, using three different molecular principles; (i) AR staining, since loss of stromal AR is directly proportional to the degree of differentiation (Gleason score), (ii) Masson staining for its role in marking reactive stroma, and (iii) spatial transcriptomics analysis. In particular, we performed a detailed analysis of spatial distribution in histologic sections at the invasive border of a tumor foci contrasting it to the tumor core. Here, we show spatially confined DEPDC1, CHN1 and CRISP3 upregulation at the invasive border with implications of signal transduction pathways such as; PTEN, TGF-beta Receptor Complex, NOTCH4, ERBB2, and VEGF signaling, some of which are druggable. Overall, our results show an unprecedented view of the molecular heterogeneity of a prostate cancer not evident by other means. Here, we reveal patient-specific gene expression hallmarks from low to aggressive cancer within the same cross section of a prostate.

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., QC 20200511