MAP3K7 loss drives enhanced androgen signaling and independently confers risk of recurrence in prostate cancer with joint loss of CHD1
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE168671 | GEO | 2021/04/12
REPOSITORIES: GEO
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Project description:Prostate cancer genomic subtypes that stratify aggressive disease and inform treatment decisions at the primary stage are currently limited. Previously, we functionally validated an aggressive subtype present in 15% of prostate cancer characterized by dual deletion of MAP3K7 and CHD1. Recent studies in the field have focused on deletion of CHD1 and its role in androgen receptor (AR) chromatin distribution and resistance to AR-targeted therapy; however, CHD1 is rarely lost without codeletion of MAP3K7. Here, we show that in the clinically relevant context of co-loss of MAP3K7 and CHD1 there are significant, collective changes to aspects of AR signaling. Although CHD1 loss mainly impacts the expansion of the AR cistrome, loss of MAP3K7 drives increased AR target gene expression. Prostate cancer cell line models engineered to cosuppress MAP3K7 and CHD1 also demonstrated increased AR-v7 expression and resistance to the AR-targeting drug enzalutamide. Furthermore, we determined that low protein expression of both genes is significantly associated with biochemical recurrence (BCR) in a clinical cohort of radical prostatectomy specimens. Low MAP3K7 expression, however, was the strongest independent predictor for risk of BCR over all other tested clinicopathologic factors including CHD1 expression. Collectively, these findings illustrate the importance of MAP3K7 loss in a molecular subtype of prostate cancer that poses challenges to conventional therapeutic approaches. IMPLICATIONS: These findings strongly implicate MAP3K7 loss as a biomarker for aggressive prostate cancer with significant risk for recurrence that poses challenges for conventional androgen receptor-targeted therapies.
| S-EPMC8254790 | biostudies-literature
Project description:MAP3K7 loss drives enhanced androgen signaling and independently confers risk of recurrence in prostate cancer with joint loss of CHD1
| PRJNA713344 | ENA
Project description:Prostate cancer subtypes are poorly defined and functional validation of drivers of ETS rearrangement-negative prostate cancer has not been conducted. Here, we identified an ETS(-) subtype of aggressive prostate cancer (ERG(-)MAP3K7(del)CHD1(del)) and used a novel developmental model and a cell line xenograft model to show that cosuppression of MAP3K7 and CHD1 expression promotes aggressive disease. Analyses of publicly available prostate cancer datasets revealed that MAP3K7 and CHD1 were significantly codeleted in 10% to 20% of localized tumors and combined loss correlated with poor disease-free survival. To evaluate the functional impact of dual MAP3K7-CHD1 loss, we suppressed Map3k7 and/or Chd1 expression in mouse prostate epithelial progenitor/stem cells (PrP/SC) and performed tissue recombination experiments in vivo. Dual shMap3k7-shChd1 PrP/SC recombinants displayed massive glandular atypia with regions of prostatic intraepithelial neoplasia and carcinoma apparent. Combined Map3k7-Chd1 suppression greatly disrupted normal prostatic lineage differentiation; dual recombinants displayed significant androgen receptor loss, increased neuroendocrine differentiation, and increased neural differentiation. Clinical samples with dual MAP3K7-CHD1 loss also displayed neuroendocrine and neural characteristics. In addition, dual Map3k7-Chd1 suppression promoted E-cadherin loss and mucin production in recombinants. MAP3K7 and CHD1 protein loss also correlated with Gleason grade and E-cadherin loss in clinical samples. To further validate the phenotype observed in the PrP/SC model, we suppressed MAP3K7 and/or CHD1 expression in LNCaP prostate cancer cells. Dual shMAP3K7-shCHD1 LNCaP xenografts displayed increased tumor growth and decreased survival compared with shControl, shMAP3K7, and shCHD1 xenografts. Collectively, these data identify coordinate loss of MAP3K7 and CHD1 as a unique driver of aggressive prostate cancer development.
| S-EPMC4531265 | biostudies-literature
Project description:BackgroundProstatic carcinoma metastatic to dura is commonly encountered at autopsy, but presenting as a dural or, especially parenchymal, brain metastasis during life is far less common. Our group has been interested in two immunohistochemical (IHC) markers previously shown to be downregulated in particularly aggressive primary prostatic carcinomas: CHD1 and MAP3K7. Here we assess protein expression in clinically-relevant CNS metastases. We also assessed how these two markers correlated with the most common genetic alteration in prostate cancer: TMPRSS2 fusion to ERG (40-60% of carcinomas at the primary site), which places ERG expression under the control of the androgen-regulated TMPRSS2 gene, increasing expression.DesignDatabase query, 2000-2016, identified 16 metastases to dura, 5 to brain parenchyma.ResultsFour of five intraparenchymal metastases and 15/16 informative dural-based metastases were ERG-negative (90.5% overall). There was reduced expression of CHD1 in 8/21 and reduced MAP3K7 in 17/21 cases; 7/19 (37%) ERG-negative metastases had dual low expression of CHD1/MAP3K7. ERG-positive cases had high expression of one or both markers.ConclusionMetastatic prostatic carcinoma to CNS demonstrates expression patterns consistent with particularly aggressive behavior. Lower ERG expression in dural and intraparenchymal metastases suggests a possibility that ERG-negative tumors with loss of MAP3K7 may become resistant to standard therapies and diffusely metastasize.
| S-EPMC6958997 | biostudies-literature
Project description:Purpose: The goal of this study is to identify genome-wide changes in AR chromatin binding that occur in a human prostate cell line with knockdown of MAP3K7(TAK1) and CHD1, in the presence and absence of androgens. We utilize this cell line as a model of an aggressive prostate cancer subtype consisting of deletions of both MAP3K7 and CHD1 in human patients. ChIP-seq comparing AR chromatin binding in shControl, shMAP3K7(TAK1), shCHD1, and both (shMAP3K7/shCHD1) was used to identify AR cistrome changes resulting from loss of each of these genes. Abstract of associated study: Prostate cancer (PCa) genomic subtypes that stratify aggressive disease and inform treatment decisions at the primary stage are currently limited. Previously, we functionally validated an aggressive subtype present in 15% of PCa characterized by dual deletion of MAP3K7 and CHD1. Recent studies in the field have focused on deletion of CHD1 and its role in androgen receptor (AR) chromatin distribution and resistance to AR-targeted therapy, however, CHD1 is rarely lost without co-deletion of MAP3K7. Here we show that in the clinically relevant context of co-loss of MAP3K7 and CHD1 there are significant, collective changes to aspects of AR signaling. While CHD1 loss mainly impacts the expansion of the AR cistrome, loss of MAP3K7 drives increased AR target gene expression. PCa cell line models engineered to co-suppress MAP3K7 and CHD1 also demonstrated increased AR-v7 expression and resistance to the AR-targeting drug enzalutamide. Furthermore, we determined that low protein expression of both genes is significantly associated with biochemical recurrence (BCR) in a clinical cohort of radical prostatectomy specimens. Low MAP3K7 expression, however, was the strongest independent predictor for risk of BCR over all other tested clinicopathologic factors including CHD1 expression. Collectively, these findings illustrate the importance of MAP3K7 loss in a molecular subtype of PCa that poses challenges to conventional therapeutic approaches.
2021-04-12 | GSE168651 | GEO
Project description:A key principle of oncolytic viral therapy is that many cancers develop defects in their antiviral responses, making them more susceptible to virus infection. However, some cancers display resistance to viral infection. Many of these resistant cancers constitutively express interferon-stimulated genes (ISGs). The goal of these experiments was to determine the role of two tumor suppressor genes, MAP3K7 and CHD1, in viral resistance and ISG expression in PC3 prostate cancer cells resistant to oncolytic vesicular stomatitis virus (VSV). MAP3K7 and CHD1 are often co-deleted in aggressive prostate cancers. Silencing expression of MAP3K7 and CHD1 in PC3 cells increased susceptibility to the matrix (M) gene mutant M51R-VSV, as shown by increased expression of viral genes, increased yield of progeny virus, and reduction of tumor growth in nude mice. Silencing MAP3K7 alone had a greater effect on virus susceptibility than did silencing CHD1. Silencing MAP3K7 and CHD1 decreased constitutive expression of ISG mRNAs and proteins, whereas silencing MAP3K7 alone decreased expression of ISG proteins, but actually increased expression of ISG mRNAs. These results suggest a role for the protein product of MAP3K7, transforming growth factor β-activated kinase 1 (TAK1), in regulating translation of ISG mRNAs and a role of CHD1 in maintaining the transcription of ISGs.
| S-EPMC7276393 | biostudies-literature
Project description:The conversion of androgen receptor (AR) signaling as a mechanism of growth suppression of normal prostate epithelial cells to that of growth stimulation in prostate cancer cells is often associated with AR mutation, amplification and over-expression. Thus, down-regulation of AR signaling is commonly therapeutic for prostate cancer. The E006AA cell line was established from a hormone naïve, localized prostate cancer. E006AA cells are genetically aneuploid and grow equally well when xenografted into either intact or castrated male NOG but not nude mice. These cells exhibit: 1) X chromosome duplication and AR gene amplification, although paradoxically not coupled with increased AR expression, and 2) somatic, dominant-negative Serine-599-Glycine loss-of-function mutation within the dimerization surface of the DNA binding domain of the AR gene. No effect on the growth of E006AA cells is observed using targeted knockdown of endogenous mutant AR, ectopic expression of wild-type AR, or treatment with androgens or anti-androgens. E006AA cells represent a prototype for a newly identified subtype of prostate cancer cells that exhibit a dominant-negative AR loss-of-function in a hormonally naïve patient. Such loss-of-function eliminates AR-mediated growth suppression normally induced by normal physiological levels of androgens, thus producing a selective growth advantage for these malignant cells in hormonally naïve patients. These data highlight that loss of AR-mediated growth suppression is an independent process, and that, without additional changes, is insufficient for acquiring oncogene addiction to AR signaling. Thus, patients with prostate cancer cells harboring such AR loss-of-function mutations will not benefit from aggressive hormone or anti-AR therapies even though they express AR protein.
| S-EPMC2900211 | biostudies-literature
Project description:AIM:The risk factors that predict surgical recurrence in Crohn's disease (CD) remain controversial. Postoperative anti-tumour necrosis factor (anti-TNF) therapy might lower recurrence rates whilst the presence of mesenteric granulomas has been postulated to increase the risk. We hypothesized that mesenteric granulomas indicate disease severity and might predict the risk of surgical recurrence, irrespective of immunosuppressive therapy. METHOD:We performed a retrospective review of all consecutive patients undergoing operations for CD between January 2000 and December 2014 at a single tertiary referral centre and assessed the perioperative factors and histological findings at the time of surgery. Surgical recurrence rates and the immunosuppressive regimen were assessed through retrospective chart review and telephone interviews. RESULTS:A total of 274 patients were eligible for analysis. Median follow-up was 8.54 (5.48-14.42) years. A total of 63 patients (23.0%) underwent surgery for recurrent CD after a median of 4.75 (2.10-7.96) years. In final histology, 35 (12.8%) patients had mesenteric granulomas. TNF inhibitors were administered postoperatively in 104 (38.0%) and thiopurines in 137 (50.0%) patients. In univariate analysis, only the presence of mesenteric granulomas [hazard ratio (HR) 1.95; 95% CI 1.05-3.62; P = 0.035] significantly increased the risk for recurrent surgery while postoperative anti-TNF (HR 0.85; 95% CI 0.49-1.50; P = 0.581) or thiopurine therapy (HR 1.03; 95% CI 0.61-1.73; P = 0.916) did not. In multivariate analysis, only the presence of mesenteric granulomas significantly influenced the risk of surgical recurrence (HR 1.94, 95% CI 1.04-3.60; P = 0.037). CONCLUSION:Intestinal and mesenteric granulomas should be differentiated in pathology reports, because mesenteric, but not intestinal, granulomas may be associated with an increased risk of surgical recurrence.
| S-EPMC7028106 | biostudies-literature
Project description:BACKGROUND:Deletions of 6q15-16.1 are recurrently found in pediatric T-cell acute lymphoblastic leukemia (T-ALL). This chromosomal region includes the mitogen-activated protein kinase kinase kinase 7 (MAP3K7) gene which has a crucial role in innate immune signaling and was observed to be functionally and prognostically relevant in different cancer entities. Therefore, we correlated the presence of MAP3K7 deletions with clinical parameters in a cohort of 327 pediatric T-ALL patients and investigated the function of MAP3K7 in the T-ALL cell lines CCRF-CEM, Jurkat and MOLT-4. METHODS:MAP3K7 deletions were detected by multiplex ligation-dependent probe amplification (MLPA). T-ALL cell lines were transduced with adeno-associated virus (AAV) vectors expressing anti-MAP3K7 shRNA or a non-silencing shRNA together with a GFP reporter. Transduction efficiency was measured by flow cytometry and depletion efficiency by RT-PCR and Western blots. Induction of apoptosis was measured by flow cytometry after staining with PE-conjugated Annexin V. In order to assess the contribution of NF-?B signaling to the effects of MAP3K7 depletion, cells were treated with TNF-? and cell lysates analyzed for components of the NF-?B pathway by Western blotting and for expression of the NF-?B target genes BCL2, CMYC, FAS, PTEN and TNF-? by RT-PCR. RESULTS:MAP3K7 is deleted in approximately 10% and point-mutated in approximately 1% of children with T-ALL. In 32 of 33 leukemias the deletion of MAP3K7 also included the adjacent CASP8AP2 gene. MAP3K7 deletions were associated with the occurrence of SIL-TAL1 fusions and a mature immunophenotype, but not with response to treatment and outcome. Depletion of MAP3K7 expression in T-ALL cell lines by shRNAs slowed down proliferation and induced apoptosis, but neither changed protein levels of components of NF-?B signaling nor NF-?B target gene expression after stimulation with TNF-?. CONCLUSIONS:This study revealed that the recurrent deletion of MAP3K7/CASP8AP2 is associated with SIL-TAL1 fusions and a mature immunophenotype, but not with response to treatment and risk of relapse. Homozygous deletions of MAP3K7 were not observed, and efficient depletion of MAP3K7 interfered with viability of T-ALL cells, indicating that a residual expression of MAP3K7 is indispensable for T-lymphoblasts.
| S-EPMC6006985 | biostudies-literature
Project description:Purpose: The goal of this study is to identify transcriptome-wide changes that occur in a human prostate cell line with knockdown of MAP3K7(TAK1) and CHD1, in the presence and absence of androgens. We utilize this cell line as a model of an aggressive prostate cancer subtype consisting of deletions of both MAP3K7 and CHD1 in human patients. RNAseq comparing shControl and shMAP3K7/shCHD1 was used to identify transcriptome changes resulting from loss of these genes, as well as their effects on androgen signaling. Abstract of associated study: Prostate cancer (PCa) genomic subtypes that stratify aggressive disease and inform treatment decisions at the primary stage are currently limited. Previously, we functionally validated an aggressive subtype present in 15% of PCa characterized by dual deletion of MAP3K7 and CHD1. Recent studies in the field have focused on deletion of CHD1 and its role in androgen receptor (AR) chromatin distribution and resistance to AR-targeted therapy, however, CHD1 is rarely lost without co-deletion of MAP3K7. Here we show that in the clinically relevant context of co-loss of MAP3K7 and CHD1 there are significant, collective changes to aspects of AR signaling. While CHD1 loss mainly impacts the expansion of the AR cistrome, loss of MAP3K7 drives increased AR target gene expression. PCa cell line models engineered to co-suppress MAP3K7 and CHD1 also demonstrated increased AR-v7 expression and resistance to the AR-targeting drug enzalutamide. Furthermore, we determined that low protein expression of both genes is significantly associated with biochemical recurrence (BCR) in a clinical cohort of radical prostatectomy specimens. Low MAP3K7 expression, however, was the strongest independent predictor for risk of BCR over all other tested clinicopathologic factors including CHD1 expression. Collectively, these findings illustrate the importance of MAP3K7 loss in a molecular subtype of PCa that poses challenges to conventional therapeutic approaches.
2021-04-12 | GSE168670 | GEO