Ratiometric Inclusion of Fibroblasts Promotes Both Castration-resistant and Androgen-dependent Tumorigenic Progression in Engineered Prostate Cancer Tissues
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE239593 | GEO | 2023/07/31
REPOSITORIES: GEO
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Project description:The neuroendocrine (NE) phenotype is associated with the development of metastatic castration-resistant prostate cancer (CRPC). Our objective was to characterize the molecular features of the NE phenotype in CRPC. Expression of chromogranin A (CHGA), synaptophysin (SYP), androgen receptor (AR), and prostate-specific antigen (PSA) was analyzed by immunohistochemistry (IHC) in 155 CRPC metastases from 50 patients and in 24 LuCaP prostate cancer patient-derived xenografts (PDX). Co-expression of CHGA and SYP in >30% of cells was observed in 22 of 155 metastases (9 patients); 11 of the 22 metastases were AR+/PSA+ (6 patients), 11/22 were AR-/PSA- (4 patients), and 4/24 LuCaP PDXs were AR-/PSA-. Seventy-one of 155 metastases and the 24 LuCaP xenograft lines were analyzed by whole genome microarrays. By IHC, of the 71 metastases analyzed by whole genome microarrays, 5 metastases were CHGA+/SYP+/AR- and 5 were CHGA+/SYP+/AR+. Only CHGA+/SYP+ metastases had a NE transcript signature. The neuronal transcriptional regulator SRRM4 transcript was associated with the NE signature in CHGA+/SYP+ metastases and all CHGA+/SYP+ LuCaP xenografts. Additionally, expression of SRRM4 in the LuCaP NE xenografts correlated with a splice variant of REST that lacks the transcriptional repressor domain. In conclusion, (a) metastatic NE status can be heterogeneous in the same patient, (b) the CRPC NE molecular phenotype can be defined by CHGA+/SYP+ dual positivity, (c) the NE phenotype is not necessarily associated with the loss of AR activity, and (d) the splicing of REST by SRRM4 could promote the NE phenotype in CRPC. Custom Agilent 44K whole human genome expression oligonucleotide microarrays were used to profile 24 LuCaP PCa xenograft lines and 71 CRPC metastases from 47 patients. RNA was amplified prior to hybridization against a common reference pool of prostate tumor cell lines.
2015-06-24 | E-GEOD-66187 | biostudies-arrayexpress
Project description:This study examined ERG expression in primary PCa and CRPC. We have identified altered levels of inflammatory mediators associated with ERG expression and a novel ERG-associated protein, DCLK1, which may play a role in primary PCa progression to metastatic CPRC.
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Project description:To inhibit the re-activation of AR-promoted tumor growth via residual androgens, more potent AR antagonists and inhibitors for androgen synthesis have been developed in the decades. While these second-generation antagonists/inhibitors showed some effectiveness clinically, they also induced more diverse castration-resistant prostate cancer (CRPC) phenotypes. Specifically, a subpopulation of AR- and neuroendocrine (NE)-null PC cells, DNPC, occurs frequently in CRPC patients treated with abiraterone and enzalutamide, increasing metastatic CRPC incidences and the mortality of prostate adenocarcinoma (PCa). Understanding the mechanisms for DNPC will directly improve clinical outcomes.
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Project description:Castration-resistant prostate cancer (CRPC) is a heterogeneous disease associated with phenotypic subtypes that drive differences in therapy response and outcomes. Histologic transformation to castration-resistant neuroendocrine prostate cancer (CRPC-NE) is associated with distinct epigenetic alterations, including acquired changes in DNA methylation. The current diagnosis of CRPC-NE is challenging and relies on metastatic biopsy. Here, we developed a targeted DNA methylation assay based on the analysis of large tissue datasets to detect CRPC-NE using plasma cell-free DNA (cfDNA) non-invasively. The assay quantifies tumor content and a phenotype evidence score that captures the spectrum of CRPC phenotypes, leveraging a few hundred informative genomic regions to also inform the expression and/or transcriptional state of genes of interest. We qualified the assay in independent clinical cohorts, including 158 plasma samples, achieving a phenotypic evidence score AUC > 0.93 for detecting pathology-confirmed CRPC-NE, and revealing associations between methylation-defined tumor content and clinical outcomes in two prospective phase 2 clinical trials (NCT01799278 and NCT00514540) designed toward aggressive variant CRPC and CRPC-NE, supporting the application of targeted DNA methylation for CRPC-NE detection and patient stratification.
2023-12-11 | GSE245745 | GEO
Project description:The neuroendocrine (NE) phenotype is associated with the development of metastatic castration-resistant prostate cancer (CRPC). Our objective was to characterize the molecular features of the NE phenotype in CRPC. Expression of chromogranin A (CHGA), synaptophysin (SYP), androgen receptor (AR), and prostate-specific antigen (PSA) was analyzed by immunohistochemistry (IHC) in 155 CRPC metastases from 50 patients and in 24 LuCaP prostate cancer patient-derived xenografts (PDX). Co-expression of CHGA and SYP in >30% of cells was observed in 22 of 155 metastases (9 patients); 11 of the 22 metastases were AR+/PSA+ (6 patients), 11/22 were AR-/PSA- (4 patients), and 4/24 LuCaP PDXs were AR-/PSA-. Seventy-one of 155 metastases and the 24 LuCaP xenograft lines were analyzed by whole genome microarrays. By IHC, of the 71 metastases analyzed by whole genome microarrays, 5 metastases were CHGA+/SYP+/AR- and 5 were CHGA+/SYP+/AR+. Only CHGA+/SYP+ metastases had a NE transcript signature. The neuronal transcriptional regulator SRRM4 transcript was associated with the NE signature in CHGA+/SYP+ metastases and all CHGA+/SYP+ LuCaP xenografts. Additionally, expression of SRRM4 in the LuCaP NE xenografts correlated with a splice variant of REST that lacks the transcriptional repressor domain. In conclusion, (a) metastatic NE status can be heterogeneous in the same patient, (b) the CRPC NE molecular phenotype can be defined by CHGA+/SYP+ dual positivity, (c) the NE phenotype is not necessarily associated with the loss of AR activity, and (d) the splicing of REST by SRRM4 could promote the NE phenotype in CRPC.
2015-06-24 | GSE66187 | GEO
Project description:Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. In patients, THEM6 expression correlates with progressive disease and is associated with poor survival. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, THEM6 is located at the endoplasmic reticulum (ER) membrane and controls lipid homeostasis by regulating intracellular levels of ether lipids. As a consequence, THEM6 loss in CRPC cells significantly alters ER function, preventing lipid-mediated induction of ATF4 and reducing de novo sterol biosynthesis. Finally, we show that THEM6 is required for the establishment of the MYC-induced stress response. Thus, similar to PCa, THEM6 loss significantly impairs tumorigenesis in the MYC-dependent subtype of triple negative breast cancer. Altogether our results highlight THEM6 as a novel component of the treatment-induced stress response and a promising target for the treatment of CRPC and MYC-driven cancer.
2021-12-11 | PXD024407 | Pride
Project description:Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. In patients, THEM6 expression correlates with progressive disease and is associated with poor survival. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, THEM6 is located at the endoplasmic reticulum (ER) membrane and controls lipid homeostasis by regulating intracellular levels of ether lipids. As a consequence, THEM6 loss in CRPC cells significantly alters ER function, preventing lipid-mediated induction of ATF4 and reducing de novo sterol biosynthesis. Finally, we show that THEM6 is required for the establishment of the MYC-induced stress response. Thus, similar to PCa, THEM6 loss significantly impairs tumorigenesis in the MYC-dependent subtype of triple negative breast cancer. Altogether our results highlight THEM6 as a novel component of the treatment-induced stress response and a promising target for the treatment of CRPC and MYC-driven cancer.
2021-12-11 | PXD024433 | Pride
Project description:Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. In patients, THEM6 expression correlates with progressive disease and is associated with poor survival. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, THEM6 is located at the endoplasmic reticulum (ER) membrane and controls lipid homeostasis by regulating intracellular levels of ether lipids. As a consequence, THEM6 loss in CRPC cells significantly alters ER function, preventing lipid-mediated induction of ATF4 and reducing de novo sterol biosynthesis. Finally, we show that THEM6 is required for the establishment of the MYC-induced stress response. Thus, similar to PCa, THEM6 loss significantly impairs tumorigenesis in the MYC-dependent subtype of triple negative breast cancer. Altogether our results highlight THEM6 as a novel component of the treatment-induced stress response and a promising target for the treatment of CRPC and MYC-driven cancer.
2021-12-11 | PXD024456 | Pride
Project description:Tumor microenvironment coevolves with and simultaneously sustains cancer progression. Reactive fibroblasts found in prostate cancer (PCa), known as cancer associated fibroblasts (CAF), have been indeed shown to fuel tumor development and metastasis by mutually interacting with PCa cells. Little is known about the molecular mechanisms that lead to activation of CAFs from tissue-resident fibroblasts, circulating marrow-derived fibroblast progenitors or mesenchymal stem cells. Through integrated gene and microRNA expression profiling, here we showed that transcriptome of CAFs isolated from prostate tumors strictly resembles that of normal fibroblasts stimulated in vitro with interleukin-6 (IL6), thus confirming the capability of the cytokine to promote acquisition of an activated and cancer-promoting phenotype, and, for the first time, proving that IL6 is able per se to induce all the complex transcriptional changes characteristic of patient-derived CAFs. Comparison with publicly available datasets, however, suggested that prostate CAFs may be alternatively characterized by IL6 and TGF?-related signatures, indicating that either signal, depending on the context, tumor stage and etiology, may concur to fibroblast activation. Our analyses also highlighted pathways relevant for induction of reactive stroma, including genes the role of which in fibroblast activation is still to be explored. In addition, we revealed a role for muscle-specific miR-133b as a soluble factor secreted by activated fibroblasts to support paracrine activation of non-activated fibroblasts or promote tumor progression. Overall, in this study we provided insights on the molecular mechanisms driving fibroblast activation in prostate cancer, thus contributing to identify novel hits for the development of therapeutic strategies targeting the crucial interplay between tumor cells and their microenvironment. Tumor microenvironment coevolves with and simultaneously sustains cancer progression. Reactive fibroblasts found in prostate cancer (PCa), known as cancer associated fibroblasts (CAF), have been indeed shown to fuel tumor development and metastasis by mutually interacting with PCa cells. Little is known about the molecular mechanisms that lead to activation of CAFs from tissue-resident fibroblasts, circulating marrow-derived fibroblast progenitors or mesenchymal stem cells. Through integrated gene and microRNA expression profiling, here we showed that transcriptome of CAFs isolated from prostate tumors strictly resembles that of normal fibroblasts stimulated in vitro with interleukin-6 (IL6), thus confirming the capability of the cytokine to promote acquisition of an activated and cancer-promoting phenotype, and, for the first time, proving that IL6 is able per se to induce all the complex transcriptional changes characteristic of patient-derived CAFs. Comparison with publicly available datasets, however, suggested that prostate CAFs may be alternatively characterized by IL6 and TGF?-related signatures, indicating that either signal, depending on the context, tumor stage and etiology, may concur to fibroblast activation. Our analyses also highlighted pathways relevant for induction of reactive stroma, including genes the role of which in fibroblast activation is still to be explored. In addition, we revealed a role for muscle-specific miR-133b as a soluble factor secreted by activated fibroblasts to support paracrine activation of non-activated fibroblasts or promote tumor progression. Overall, in this study we provided insights on the molecular mechanisms driving fibroblast activation in prostate cancer, thus contributing to identify novel hits for the development of therapeutic strategies targeting the crucial interplay between tumor cells and their microenvironment. Tumor microenvironment coevolves with and simultaneously sustains cancer progression. Reactive fibroblasts found in prostate cancer (PCa), known as cancer associated fibroblasts (CAF), have been indeed shown to fuel tumor development and metastasis by mutually interacting with PCa cells. Little is known about the molecular mechanisms that lead to activation of CAFs from tissue-resident fibroblasts, circulating marrow-derived fibroblast progenitors or mesenchymal stem cells. Through integrated gene and microRNA expression profiling, here we showed that transcriptome of CAFs isolated from prostate tumors strictly resembles that of normal fibroblasts stimulated in vitro with interleukin-6 (IL6), thus confirming the capability of the cytokine to promote acquisition of an activated and cancer-promoting phenotype, and, for the first time, proving that IL6 is able per se to induce all the complex transcriptional changes characteristic of patient-derived CAFs. Comparison with publicly available datasets, however, suggested that prostate CAFs may be alternatively characterized by IL6 and TGF?-related signatures, indicating that either signal, depending on the context, tumor stage and etiology, may concur to fibroblast activation. Our analyses also highlighted pathways relevant for induction of reactive stroma, including genes the role of which in fibroblast activation is still to be explored. In addition, we revealed a role for muscle-specific miR-133b as a soluble factor secreted by activated fibroblasts to support paracrine activation of non-activated fibroblasts or promote tumor progression. Overall, in this study we provided insights on the molecular mechanisms driving fibroblast activation in prostate cancer, thus contributing to identify novel hits for the development of therapeutic strategies targeting the crucial interplay between tumor cells and their microenvironment. In the present study, patient derived-CAFs and HPFs activated in vitro with either TGF? or IL6 were comparatively analyzed for gene and microRNA (miRNA) expression profiles, with the aim to define transcriptional pathways responsible for fibroblast activation and establish whether different subpopulations of CAFs may exist in PCa.
2015-09-01 | E-GEOD-68164 | biostudies-arrayexpress
Project description:Tumor microenvironment coevolves with and simultaneously sustains cancer progression. Reactive fibroblasts found in prostate cancer (PCa), known as cancer associated fibroblasts (CAF), have been indeed shown to fuel tumor development and metastasis by mutually interacting with PCa cells. Little is known about the molecular mechanisms that lead to activation of CAFs from tissue-resident fibroblasts, circulating marrow-derived fibroblast progenitors or mesenchymal stem cells. Through integrated gene and microRNA expression profiling, here we showed that transcriptome of CAFs isolated from prostate tumors strictly resembles that of normal fibroblasts stimulated in vitro with interleukin-6 (IL6), thus confirming the capability of the cytokine to promote acquisition of an activated and cancer-promoting phenotype, and, for the first time, proving that IL6 is able per se to induce all the complex transcriptional changes characteristic of patient-derived CAFs. Comparison with publicly available datasets, however, suggested that prostate CAFs may be alternatively characterized by IL6 and TGFβ-related signatures, indicating that either signal, depending on the context, tumor stage and etiology, may concur to fibroblast activation. Our analyses also highlighted pathways relevant for induction of reactive stroma, including genes the role of which in fibroblast activation is still to be explored. In addition, we revealed a role for muscle-specific miR-133b as a soluble factor secreted by activated fibroblasts to support paracrine activation of non-activated fibroblasts or promote tumor progression. Overall, in this study we provided insights on the molecular mechanisms driving fibroblast activation in prostate cancer, thus contributing to identify novel hits for the development of therapeutic strategies targeting the crucial interplay between tumor cells and their microenvironment. Tumor microenvironment coevolves with and simultaneously sustains cancer progression. Reactive fibroblasts found in prostate cancer (PCa), known as cancer associated fibroblasts (CAF), have been indeed shown to fuel tumor development and metastasis by mutually interacting with PCa cells. Little is known about the molecular mechanisms that lead to activation of CAFs from tissue-resident fibroblasts, circulating marrow-derived fibroblast progenitors or mesenchymal stem cells. Through integrated gene and microRNA expression profiling, here we showed that transcriptome of CAFs isolated from prostate tumors strictly resembles that of normal fibroblasts stimulated in vitro with interleukin-6 (IL6), thus confirming the capability of the cytokine to promote acquisition of an activated and cancer-promoting phenotype, and, for the first time, proving that IL6 is able per se to induce all the complex transcriptional changes characteristic of patient-derived CAFs. Comparison with publicly available datasets, however, suggested that prostate CAFs may be alternatively characterized by IL6 and TGFβ-related signatures, indicating that either signal, depending on the context, tumor stage and etiology, may concur to fibroblast activation. Our analyses also highlighted pathways relevant for induction of reactive stroma, including genes the role of which in fibroblast activation is still to be explored. In addition, we revealed a role for muscle-specific miR-133b as a soluble factor secreted by activated fibroblasts to support paracrine activation of non-activated fibroblasts or promote tumor progression. Overall, in this study we provided insights on the molecular mechanisms driving fibroblast activation in prostate cancer, thus contributing to identify novel hits for the development of therapeutic strategies targeting the crucial interplay between tumor cells and their microenvironment. Tumor microenvironment coevolves with and simultaneously sustains cancer progression. Reactive fibroblasts found in prostate cancer (PCa), known as cancer associated fibroblasts (CAF), have been indeed shown to fuel tumor development and metastasis by mutually interacting with PCa cells. Little is known about the molecular mechanisms that lead to activation of CAFs from tissue-resident fibroblasts, circulating marrow-derived fibroblast progenitors or mesenchymal stem cells. Through integrated gene and microRNA expression profiling, here we showed that transcriptome of CAFs isolated from prostate tumors strictly resembles that of normal fibroblasts stimulated in vitro with interleukin-6 (IL6), thus confirming the capability of the cytokine to promote acquisition of an activated and cancer-promoting phenotype, and, for the first time, proving that IL6 is able per se to induce all the complex transcriptional changes characteristic of patient-derived CAFs. Comparison with publicly available datasets, however, suggested that prostate CAFs may be alternatively characterized by IL6 and TGFβ-related signatures, indicating that either signal, depending on the context, tumor stage and etiology, may concur to fibroblast activation. Our analyses also highlighted pathways relevant for induction of reactive stroma, including genes the role of which in fibroblast activation is still to be explored. In addition, we revealed a role for muscle-specific miR-133b as a soluble factor secreted by activated fibroblasts to support paracrine activation of non-activated fibroblasts or promote tumor progression. Overall, in this study we provided insights on the molecular mechanisms driving fibroblast activation in prostate cancer, thus contributing to identify novel hits for the development of therapeutic strategies targeting the crucial interplay between tumor cells and their microenvironment. In the present study, patient derived-CAFs and HPFs activated in vitro with either TGFβ or IL6 were comparatively analyzed for gene and microRNA (miRNA) expression profiles, with the aim to define transcriptional pathways responsible for fibroblast activation and establish whether different subpopulations of CAFs may exist in PCa.
2015-09-01 | E-GEOD-68165 | biostudies-arrayexpress