scholarly journals Transcriptional mediators of treatment resistance in lethal prostate cancer

2020 ◽  
Author(s):  
Meng Xiao He ◽  
Michael S. Cuoco ◽  
Jett Crowdis ◽  
Alice Bosma-Moody ◽  
Zhenwei Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Significant Proportion ◽  
Treatment Resistance ◽  
Treatment Modalities ◽  
Castration Resistant Prostate Cancer ◽  
Mesenchymal Transition ◽  
Clinical Resistance

ABSTRACTMetastatic castration resistant prostate cancer (mCRPC) is primarily treated with therapies that prevent transcriptional activity of the androgen receptor (AR), cause DNA damage, or prevent cell division. Clinical resistance to these therapies, including second-generation androgen-targeting compounds such as enzalutamide and abiraterone, is nearly universal. Other treatment modalities, including immune checkpoint inhibitors, have provided minimal benefit except in rare subsets of patients1,2. Both tumour intrinsic and extrinsic cellular programs contributing to therapeutic resistance remain areas of active investigation. Here we use full-length single-cell RNA-sequencing (scRNA-seq) to identify the transcriptional states of cancer and immune cells in the mCRPC microenvironment. Within cancer cells, we identified transcriptional patterns that mediate a significant proportion of inherited risk for prostate cancer, extensive heterogeneity in AR splicing within and between tumours, and vastly divergent regulatory programs between adenocarcinoma and small cell carcinoma. Moreover, upregulation of TGF-β signalling and epithelial-mesenchymal transition (EMT) were both associated with resistance to enzalutamide. We found that some lymph node metastases, but no bone metastases, were heavily infiltrated by dysfunctional CD8+ T cells, including cells undergoing dramatic clonal expansion during enzalutamide treatment. Our findings suggest avenues for rational therapeutic approaches targeting both tumour-intrinsic and immunological pathways to combat resistance to current treatment options.

scholarly journals Transcriptional mediators of treatment resistance in lethal prostate cancer

2021 ◽  
Author(s):  
Meng Xiao He ◽  
Michael S. Cuoco ◽  
Jett Crowdis ◽  
Alice Bosma-Moody ◽  
Zhenwei Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Transforming Growth Factor Β ◽  
Castration Resistant Prostate Cancer ◽  
Mesenchymal Transition ◽  
Castration Resistant

AbstractMetastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors1. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies2,3. Resistance to enzalutamide was associated with cancer cell–intrinsic epithelial–mesenchymal transition and transforming growth factor-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. 4–6). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8+ T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.

scholarly journals Chromatin-directed proteomics-identified network of endogenous androgen receptor in prostate cancer cells

Oncogene ◽  
2021 ◽  
Author(s):  
Kaisa-Mari Launonen ◽  
Ville Paakinaho ◽  
Gianluca Sigismondo ◽  
Marjo Malinen ◽  
Reijo Sironen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Protein A ◽  
Chorioallantoic Membrane ◽  
Chromatin Accessibility ◽  
Castration Resistant Prostate Cancer ◽  
Novel Therapy ◽  
Mesenchymal Transition

AbstractTreatment of prostate cancer confronts resistance to androgen receptor (AR)-targeted therapies. AR-associated coregulators and chromatin proteins hold a great potential for novel therapy targets. Here, we employed a powerful chromatin-directed proteomics approach termed ChIP-SICAP to uncover the composition of chromatin protein network, the chromatome, around endogenous AR in castration resistant prostate cancer (CRPC) cells. In addition to several expected AR coregulators, the chromatome contained many nuclear proteins not previously associated with the AR. In the context of androgen signaling in CRPC cells, we further investigated the role of a known AR-associated protein, a chromatin remodeler SMARCA4 and that of SIM2, a transcription factor without a previous association with AR. To understand their role in chromatin accessibility and AR target gene expression, we integrated data from ChIP-seq, RNA-seq, ATAC-seq and functional experiments. Despite the wide co-occurrence of SMARCA4 and AR on chromatin, depletion of SMARCA4 influenced chromatin accessibility and expression of a restricted set of AR target genes, especially those involved in cell morphogenetic changes in epithelial-mesenchymal transition. The depletion also inhibited the CRPC cell growth, validating SMARCA4’s functional role in CRPC cells. Although silencing of SIM2 reduced chromatin accessibility similarly, it affected the expression of a much larger group of androgen-regulated genes, including those involved in cellular responses to external stimuli and steroid hormone stimulus. The silencing also reduced proliferation of CRPC cells and tumor size in chick embryo chorioallantoic membrane assay, further emphasizing the importance of SIM2 in CRPC cells and pointing to the functional relevance of this potential prostate cancer biomarker in CRPC cells. Overall, the chromatome of AR identified in this work is an important resource for the field focusing on this important drug target.

scholarly journals Epithelial Transcription Factor FOXA1 Regulates Prostate Cancer Immune Response

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1017-A1017
Author(s):  
Lourdes T Brea ◽  
Xiaohai Wang ◽  
Jindan Yu
Keyword(s):  
Prostate Cancer ◽  
Immune Response ◽  
Transcription Factor ◽  
Inflammatory Response ◽  
Epithelial Mesenchymal Transition ◽  
Checkpoint Inhibitors ◽  
Macrophage Infiltration ◽  
Dependent Manner ◽  
Rna Seq ◽  
Mesenchymal Transition

Abstract Background : While localized prostate cancer (PCa) can be mitigated by surgery and radiation, metastatic PCa remains a challenge to treat. Androgen deprivation therapies and androgen receptor (AR) pathway inhibitors are mainstay treatments for advanced PCa. Yet, resistance often develops leading to castration-resistant prostate cancer (CRPC). Forkhead Box A1 (FOXA1) is a pioneer transcription factor that plays pivotal roles in regulating AR activity and promoting epithelial differentiation. Studies have shown that FOXA1 is frequently downregulated in CRPC tumors. Congruently, FOXA1 loss is reported to induce aberrant AR signaling, epithelial-mesenchymal transition, and PCa de-differentiation. However, the role of FOXA1 in regulating PCa immune response, an area of much interest recently, has not been reported. CRPC has shown poor response to immune checkpoint inhibitors, due to its immunosuppressive nature. A better understanding of the tumor intrinsic mechanisms regulating PCa tumor immunity will inform the design of better targeted immunotherapeutic approaches. Methods: We performed RNA-seq, ChIP-seq, qPCR, western blot, and ELISA analyses to evaluate how FOXA1 regulates inflammatory response genes. We utilized an in vitro macrophage infiltration transwell assay, in which M2-like macrophages were added to the upper chamber and PCa cells were plated in the lower chamber, to examine how perturbations to PCa cells affect macrophage migration. Finally, we performed bioinformatic analyses of patient datasets to confirm the clinical relevance of FOXA1 repression of inflammatory genes in PCa. Results: Through integration of RNA-seq and ChIP-seq data, we uncovered a novel function of FOXA1 in suppressing inflammatory response pathways. In accordance, patient data analyses revealed that inflammatory response genes were upregulated in FOXA1-low PCa tumors. Mechanistically, we showed that FOXA1 proteins bound an intragenic enhancer of Hypoxia-inducible factor 1-alpha (HIF1A) gene to directly repress its expression, such that FOXA1 loss induced HIF1A upregulation. We further showed that Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) became upregulated upon FOXA1 depletion in a HIF1A-dependent manner. This led to infiltration by immunosuppressive, tumor promoting M2-like macrophages. Inhibiting this HIF1A-CCL2 axis with a HIF1A inhibitor or CCL2 neutralizing antibody blocked macrophage infiltration. Future studies using immunocompetent mouse models are needed to confirm the effect of FOXA1 on macrophage infiltration in vivo and evaluate the preclinical potential of targeting the FOXA1-HIF1A-CCL2 axis in CRPC. Conclusion: This study proposes a novel role for FOXA1 loss in promoting macrophage infiltration via the HIF1A-CCL2 axis. Moreover, our findings suggest that targeting this axis may be a promising approach for the treatment of FOXA1-low CRPC tumors.

scholarly journals Nerve Growth Factor Induces Proliferation and Aggressiveness in Prostate Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 784 ◽  
Author(s):  
Marzia Di Donato ◽  
Gustavo Cernera ◽  
Antimo Migliaccio ◽  
Gabriella Castoria
Keyword(s):  
Prostate Cancer ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Tyrosine Kinase Receptor ◽  
Primary Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Antitumor Effects ◽  
Nerve Growth ◽  
Mesenchymal Transition

Resistance to hormone therapy and disease progression is the major challenge in clinical management of prostate cancer (PC). Drugs currently used in PC therapy initially show a potent antitumor effects, but PC gradually develops resistance, relapses and spreads. Most patients who fail primary therapy and have recurrences eventually develop castration-resistant prostate cancer (CRPC), which is almost incurable. The nerve growth factor (NGF) acts on a variety of non-neuronal cells by activating the NGF tyrosine-kinase receptor, tropomyosin receptor kinase A (TrkA). NGF signaling is deregulated in PC. In androgen-dependent PC cells, TrkA mediates the proliferative action of NGF through its crosstalk with the androgen receptor (AR). Epithelial PC cells, however, acquire the ability to express NGF and TrkA, as the disease progresses, indicating a role for NGF/TrkA axis in PC progression and androgen-resistance. We here report that once activated by NGF, TrkA mediates proliferation, invasiveness and epithelial-mesenchymal transition (EMT) in various CRPC cells. NGF promotes organoid growth in 3D models of CRPC cells, and specific inhibition of TrkA impairs all these responses. Thus TrkA represents a new biomarker to target in CRPC.

Got central prostate pathology review? A cross-sectional audit of 2009 versus 2003 outcomes.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 196-196
Author(s):  
N. D'Souza ◽  
D. A. Loblaw ◽  
A. Mamedov ◽  
E. Klotz ◽  
L. Sugar ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Gleason Score ◽  
Strong Predictor ◽  
Treatment Options ◽  
Significant Proportion ◽  
Consensus Conference ◽  
Treatment Modalities ◽  
Risk Category ◽  
Cross Sectional ◽  
Cancer Management

196 Background: Prostate cancer is the most common non-cutaneous cancer in Canadian men; over 24,000 will be newly diagnosed and 4,300 will die from it in 2010. Estimating an individual's risk of disease spreading across the capsule and probability of recurrence with different treatment modalities is common practice in prostate cancer management and often drive the choice or extent of treatment options. A strong predictor of recurrence and organ confined disease is tumor grade. The literature recognizes differences in grading prostate cancer between genitourinary and non-specialized pathologists; we previously reported a 30% change in risk category (Low, GS 2-6; Int., GS 7; High, GS 8-10). However, this report was based on data from 2003/2004. A repeat audit was necessary given Gleason grading practice changes following the 2005 ISUP Consensus Conference. Methods: Log books from 2009/10 where our Genitourinary Pathologists (GUP) reviewed prostate needle core biopsies were used to identify cases; a retrospective chart review was completed. The following variables were extracted: 1° Gleason score; 2° Gleason score; number of sites; % Gleason 4/5 pattern (overall); perineural invasion (present/absent); extracapsular extension (present/absent). Descriptive statistics were used to summarize the results. Results: The charts of 132 patients having a GUP biopsy review were extracted. Seventeen percent (22/132) of cases changed risk category. Of the 47 low risk cases, 23% (11/47) were up-graded in risk category (21% by 1 category; 2% by 2 categories). Of the 46 intermediate risk cases, 15% (7/46) were up-graded and 2% (1/46) were down-graded. Of the 39 high risk cases, only 8% (3/39) were down-graded by 1 risk category. Comparatively, there was a 43% reduction in risk category change between 2003/04 (30%) and 2009/10 (17%). Conclusions: Despite this reduction, a clinically significant proportion of patients changed pathologic risk category upon GUP review. Thus, it is recommended that prostate cancer pathology be routinely reviewed by a GUP as a best practice to optimize management and quality of care. Strategies are still needed to address disparities in pathologic grading and represent a potential area for further investigation. No significant financial relationships to disclose.

scholarly journals Enzalutamide therapy for advanced prostate cancer: efficacy, resistance and beyond

2019 ◽  
Vol 26 (1) ◽  
pp. R31-R52 ◽  
Author(s):  
Simon Linder ◽  
Henk G van der Poel ◽  
Andries M Bergman ◽  
Wilbert Zwart ◽  
Stefan Prekovic
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Advanced Prostate Cancer ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Treatment Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Optimal Sequence ◽  
Castration Resistant ◽  
Novel Drugs

The androgen receptor drives the growth of metastatic castration-resistant prostate cancer. This has led to the development of multiple novel drugs targeting this hormone-regulated transcription factor, such as enzalutamide – a potent androgen receptor antagonist. Despite the plethora of possible treatment options, the absolute survival benefit of each treatment separately is limited to a few months. Therefore, current research efforts are directed to determine the optimal sequence of therapies, discover novel drugs effective in metastatic castration-resistant prostate cancer and define patient subpopulations that ultimately benefit from these treatments. Molecular studies provide evidence on which pathways mediate treatment resistance and may lead to improved treatment for metastatic castration-resistant prostate cancer. This review provides, firstly a concise overview of the clinical development, use and effectiveness of enzalutamide in the treatment of advanced prostate cancer, secondly it describes translational research addressing enzalutamide response vs resistance and lastly highlights novel potential treatment strategies in the enzalutamide-resistant setting.

scholarly journals Immunosuppressive microenvironment in oral cancer: implications for cancer immunotherapy

2021 ◽  
Author(s):  
Shalini K. SureshBabu ◽  
Jueelee H. Godbole ◽  
Anand Vaibhaw ◽  
Shubhada V. Chiplunkar
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Treatment Options ◽  
Locally Advanced ◽  
Immune Surveillance ◽  
Suppressor Cell ◽  
Therapy Resistance ◽  
Vital Role ◽  
Treatment Modalities ◽  
Mesenchymal Transition ◽  
The Impact

Head and neck squamous cell carcinoma (HNSCC) is a relatively widespread cancer with high mortality rates. Many patients with locally advanced disease are treated with combinations of surgery, radiation, and chemotherapy, while others are considered incurable and develop recurrent/metastatic(R/M) disease. Despite these treatment modalities, the 5-year survival rate of HNSCC has remained at 50% due to limited treatment options in patients with recurrent disease. Immunotherapy has been shown to induce durable responses in R/M patients, but only a minority of patients currently respond. A major hurdle in tumor immunotherapy is identifying the non-responders and markers to predict resistance in patients who at first responded to the therapy. In HNSCC patients, the tumor microenvironment (TME) assumes a vital role to either diminish or augment immune responses. There is an urgent need for extensive studies to be undertaken to better understand how tumor cells escape immune surveillance and resist immune attack. In this review, the impact of TME on the efficiency of immunotherapy, addressing the factors that mediate therapy resistance are highlighted. The composition of the TME encompassing the immunosuppressive cells including myeloid-derived suppressor cell (MDSC), regulatory T cells (Treg), mesenchymal stem cell (MSC), cancer-associated fibroblast (CAF), and tumor-associated macrophages (TAMs) and intrinsic factors like hypoxia, reactive oxygen species (ROS),extracellular matrix (ECM), angiogenesis, and epithelial-mesenchymal transition (EMT), how this debilitates immunosurveillance, and also discuss existing and potential strategies aimed at targeting these cellular and molecular TME components are reviewed. Understanding the interactions between the TME and immunotherapy is not only important in dissevering the mechanisms of action of immunosuppression but also offers scope for developing newer strategies to improve the competence of current immunotherapies.

scholarly journals Identification of Key Genes and Molecular Mechanisms Associated With Docetaxel Resistance in Castration Resistant Prostate Cancer Based on Bioinformatics Analysis

2020 ◽  
Author(s):  
Yu Liu ◽  
Changpeng Hu ◽  
Qian Zhang ◽  
Wuyi Liu ◽  
Guobing Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Castration Resistant Prostate Cancer ◽  
Mesenchymal Transition ◽  
Docetaxel Resistance ◽  
Castration Resistant ◽  
E2f Transcription Factor ◽  
Key Genes

Abstract BackgroundCastration resistant prostate cancer (CRPC) is one of the most common solid tumor with high mortality and limited therapeutic options, and docetaxel is the first-line chemotherapy for patients. However, the long-term use of docetaxel has limited its clinical applications. The aim of this study was to identify docetaxel-resistant key genes and molecular mechanisms. ResultsTUBB4A (Class IVa beta-tubulin), SRPX (Sushi repeat containing protein, X chromosome) and CSRP2 (Cysteine and glycine rich protein 2) were finally identified as the key genes tightly related to docetaxel resistance. TUBB4A and CSRP2 may participate in docetaxel resistance by E2F transcription factor and MYC proto-Oncogene in the process of cell cycle, and SRPX may participate in docetaxel resistance by epithelial–mesenchymal transition (EMT) and P53 pathway. ConclusionTUBB4A, SRPX and CSRP2 may be the key genes associated with docetaxel resistance, which could be prognostic biomarkers for docetaxel resistance in CRPC.

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