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The Journal of Clinical Investigation Dec 2023Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting...
Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting cancer cell lineage plasticity are scarcely identified. Here, we found that a G protein-coupled receptor, ADORA2A, is specifically upregulated during neuroendocrine differentiation, a common form of lineage plasticity in prostate cancer and lung cancer following targeted therapies. Activation of the ADORA2A signaling rewires the proline metabolism via an ERK/MYC/PYCR cascade. Increased proline synthesis promotes deacetylases SIRT6/7-mediated deacetylation of histone H3 at lysine 27 (H3K27), and thereby biases a global transcriptional output toward a neuroendocrine lineage profile. Ablation of Adora2a in genetically engineered mouse models inhibits the development and progression of neuroendocrine prostate and lung cancers, and, intriguingly, prevents the adenocarcinoma-to-neuroendocrine phenotypic transition. Importantly, pharmacological blockade of ADORA2A profoundly represses neuroendocrine prostate and lung cancer growth in vivo. Therefore, we believe that ADORA2A can be used as a promising therapeutic target to govern the epigenetic reprogramming in neuroendocrine malignancies.
Topics: Animals; Humans; Male; Mice; Cell Line, Tumor; Epigenesis, Genetic; Lung Neoplasms; Proline; Prostate; Prostatic Neoplasms; Sirtuins
PubMed: 38099497
DOI: 10.1172/JCI168670 -
Molecular Cancer Oct 2023Genetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling...
Genetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling methods could confound accurate assessment. Based on previously published spatial transcriptomic data from multifocal prostate cancer, we created virtual biopsy models that mimic conventional biopsy placement and core size. We then analysed the gene expression of different prognostic signatures (OncotypeDx®, Decipher®, Prostadiag®) using a step-wise approach with increasing resolution from pseudo-bulk analysis of the whole biopsy, to differentiation by tissue subtype (benign, stroma, tumour), followed by distinct tumour grade and finally clonal resolution. The gene expression profile of virtual tumour biopsies revealed clear differences between grade groups and tumour clones, compared to a benign control, which were not reflected in bulk analyses. This suggests that bulk analyses of whole biopsies or tumour-only areas, as used in clinical practice, may provide an inaccurate assessment of gene profiles. The type of tissue, the grade of the tumour and the clonal composition all influence the gene expression in a biopsy. Clinical decision making based on biopsy genomics should be made with caution while we await more precise targeting and cost-effective spatial analyses.
Topics: Male; Humans; Prostate; Transcriptome; Biopsy; Prostatic Neoplasms; Genomics
PubMed: 37789377
DOI: 10.1186/s12943-023-01863-2 -
Journal of Nuclear Medicine : Official... Dec 2023Ra-dichloride (Ra) and Lu-prostate-specific membrane antigen (PSMA) are approved treatments for metastatic castration-resistant prostate cancer (mCRPC). The safety and...
Ra-dichloride (Ra) and Lu-prostate-specific membrane antigen (PSMA) are approved treatments for metastatic castration-resistant prostate cancer (mCRPC). The safety and effectiveness of sequential use of Ra and Lu-PSMA in patients with mCRPC are not well described. This study aimed to evaluate Lu-PSMA safety and efficacy in patients with mCRPC previously treated with Ra. The radium→lutetium (RALU) study was a multicenter, retrospective, medical chart review. Participants had received at least 1 Ra dose and, in any subsequent therapy line, at least 1 Lu-PSMA dose. Primary endpoints included the incidence of adverse events (AEs), serious AEs, grade 3-4 hematologic AEs, and abnormal laboratory values. Secondary endpoints included overall survival, time to next treatment/death, and change from baseline in serum prostate-specific antigen and alkaline phosphatase levels. Data were from 133 patients. Before Lu-PSMA therapy, 56% (75/133) of patients received at least 4 life-prolonging therapies; all patients received Ra (73% received 5-6 injections). Overall, 27% (36/133) of patients received at least 5 Lu-PSMA infusions. Any-grade treatment-emergent AEs were reported in 79% (105/133) of patients and serious AEs in 30% (40/133). The most frequent grade 3-4 laboratory abnormalities were anemia (30%, 40/133) and thrombocytopenia (13%, 17/133). Median overall survival was 13.2 mo (95% CI, 10.5-15.6 mo) from the start of Lu-PSMA. In this real-world setting, Ra followed by Lu-PSMA therapy in heavily pretreated patients with mCRPC was clinically feasible, with no indication of impairment of Lu-PSMA safety or effectiveness.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Lutetium; Radium; Treatment Outcome; Retrospective Studies; Prostate; Radiopharmaceuticals; Prostate-Specific Antigen; Dipeptides; Heterocyclic Compounds, 1-Ring
PubMed: 37827838
DOI: 10.2967/jnumed.123.266125 -
International Journal of Molecular... Sep 2023Extracellular vesicles (EVs)-including apoptotic bodies, microvesicles, and exosomes-are released by almost all cell types and contain molecular footprints from their... (Review)
Review
Extracellular vesicles (EVs)-including apoptotic bodies, microvesicles, and exosomes-are released by almost all cell types and contain molecular footprints from their cell of origin, including lipids, proteins, metabolites, RNA, and DNA. They have been successfully isolated from blood, urine, semen, and other body fluids. In this review, we discuss the current understanding of the predictive value of EVs in prostate and renal cancer. We also describe the findings supporting the use of EVs from liquid biopsies in stratifying high-risk prostate/kidney cancer and advanced disease, such as castration-resistant (CRPC) and neuroendocrine prostate cancer (NEPC) as well as metastatic renal cell carcinoma (RCC). Assays based on EVs isolated from urine and blood have the potential to serve as highly sensitive diagnostic studies as well as predictive measures of tumor recurrence in patients with prostate and renal cancers. Overall, we discuss the biogenesis, isolation, liquid-biopsy, and therapeutic applications of EVs in CRPC, NEPC, and RCC.
Topics: Male; Humans; Carcinoma, Renal Cell; Prostate; Prostatic Neoplasms, Castration-Resistant; Clinical Relevance; Kidney Neoplasms; Neoplasm Recurrence, Local; Extracellular Vesicles; Exosomes
PubMed: 37834162
DOI: 10.3390/ijms241914713 -
Theranostics 2024Neuroendocrine prostate cancer (NEPC) typically implies severe lethality and limited treatment options. The precise identification of NEPC cells holds paramount...
Neuroendocrine prostate cancer (NEPC) typically implies severe lethality and limited treatment options. The precise identification of NEPC cells holds paramount significance for both research and clinical applications, yet valid NEPC biomarker remains to be defined. Leveraging 11 published NE-related gene sets, 11 single-cell RNA-sequencing (scRNA-seq) cohorts, 15 bulk transcriptomic cohorts, and 13 experimental models of prostate cancer (PCa), we employed multiple advanced algorithms to construct and validate a robust NEPC risk prediction model. Through the compilation of a comprehensive scRNA-seq reference atlas (comprising a total of 210,879 single cells, including 66 tumor samples) from 9 multicenter datasets of PCa, we observed inconsistent and inefficient performance among the 11 published NE gene sets. Therefore, we developed an integrative analysis pipeline, identifying 762 high-quality NE markers. Subsequently, we derived the NE cell-intrinsic gene signature, and developed an R package named NEPAL, to predict NEPC risk scores. By applying to multiple independent validation datasets, NEPAL consistently and accurately assigned NE feature and delineated PCa progression. Intriguingly, NEPAL demonstrated predictive capabilities for prognosis and therapy responsiveness, as well as the identification of potential epigenetic drivers of NEPC. The present study furnishes a valuable tool for the identification of NEPC and the monitoring of PCa progression through transcriptomic profiles obtained from both bulk and single-cell sources.
Topics: Male; Humans; Neuroendocrine Cells; Prostatic Neoplasms; Prostate; Gene Expression Profiling; Transcriptome
PubMed: 38250042
DOI: 10.7150/thno.92336 -
Oncogene Jul 2023Tuft cells are chemosensory epithelial cells that increase in number following infection or injury to robustly activate the innate immune response to alleviate or...
Tuft cells are chemosensory epithelial cells that increase in number following infection or injury to robustly activate the innate immune response to alleviate or promote disease. Recent studies of castration resistant prostate cancer and its subtype, neuroendocrine prostate cancer, revealed Pou2f3+ populations in mouse models. The transcription factor Pou2f3 is a master regulator of the tuft cell lineage. We show that tuft cells are upregulated early during prostate cancer development, and their numbers increase with progression. Cancer-associated tuft cells in the mouse prostate express DCLK1, COX1, COX2, while human tuft cells express COX1. Mouse and human tuft cells exhibit strong activation of signaling pathways including EGFR and SRC-family kinases. While DCLK1 is a mouse tuft cell marker, it is not present in human prostate tuft cells. Tuft cells that appear in mouse models of prostate cancer display genotype-specific tuft cell gene expression signatures. Using bioinformatic analysis tools and publicly available datasets, we characterized prostate tuft cells in aggressive disease and highlighted differences between tuft cell populations. Our findings indicate that tuft cells contribute to the prostate cancer microenvironment and may promote development of more advanced disease. Further research is needed to understand contributions of tuft cells to prostate cancer progression.
Topics: Male; Mice; Humans; Animals; Prostate; Protein Serine-Threonine Kinases; Signal Transduction; Prostatic Neoplasms; Epithelial Cells; Tumor Microenvironment; Doublecortin-Like Kinases
PubMed: 37386128
DOI: 10.1038/s41388-023-02743-1 -
Frontiers in Endocrinology 2023Androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, and the development of castrate-resistant prostate cancer (CRPC) is the primary... (Review)
Review
Androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, and the development of castrate-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-related mortality. While CRPC typically develops through a gain in androgen receptor (AR) signaling, a subset of CRPC will lose reliance on the AR. This process involves genetic, epigenetic, and hormonal changes that promote cellular plasticity, leading to AR-indifferent disease, with neuroendocrine prostate cancer (NEPC) being the quintessential example. NEPC is enriched following treatment with second-generation anti-androgens and exhibits resistance to endocrine therapy. Loss of , , and expression and and amplification appear to be key drivers for NEPC differentiation. Epigenetic modifications also play an important role in the transition to a neuroendocrine phenotype. DNA methylation of specific gene promoters can regulate lineage commitment and differentiation. Histone methylation can suppress AR expression and promote neuroendocrine-specific gene expression. Emerging data suggest that EZH2 is a key regulator of this epigenetic rewiring. Several mechanisms drive AR-dependent castration resistance, notably AR splice variant expression, expression of the adrenal-permissive 3βHSD1 allele, and glucocorticoid receptor expression. Aberrant epigenetic regulation also promotes radioresistance by altering the expression of DNA repair- and cell cycle-related genes. Novel therapies are currently being developed to target these diverse genetic, epigenetic, and hormonal mechanisms promoting lineage plasticity-driven NEPC.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Epigenesis, Genetic; Androgen Antagonists; Prostate
PubMed: 37455903
DOI: 10.3389/fendo.2023.1191311 -
International Journal of Molecular... Jul 2023Benign prostatic hyperplasia (BPH) is a chronic proliferative disease showing stromal-dominant proliferation. However, the detailed proliferation mechanism has remained... (Review)
Review
Benign prostatic hyperplasia (BPH) is a chronic proliferative disease showing stromal-dominant proliferation. However, the detailed proliferation mechanism has remained unclear. Although aging and androgen have been reported as definitive risk factors for BPH, recent studies have focused on the involvement of androgen-independent factors. Androgen-independent factors include ischemia, oxidative stress, metabolic syndrome, infection, autoimmune reactions, and inflammation, with inflammation in BPH tissues playing a central role in the BPH proliferative process. Inflammation in BPH tissues by various factors finally leads to tissue remodeling and stromal proliferation through the wound healing process of the prostate. To elucidate the proliferative mechanism of BPH, a study using whole-genome gene expression analysis in a stromal-dominant BPH rat model was performed and showed that immune response-related pathways and complement classical pathways are activated. Furthermore, expression analysis using this BPH rat model showed that the autoimmune reaction triggered complement pathway activation in the proliferative process of BPH. BPH is a multifactorial disease, and understanding the role of androgen-independent factors including immune responses contributes to elucidating the pathogenesis of BPH. Androgen-independent factors may lead to new therapeutic targets for BPH, and further development of this research is expected.
Topics: Humans; Male; Rats; Animals; Prostatic Hyperplasia; Androgens; Prostate; Inflammation; Cell Proliferation
PubMed: 37511400
DOI: 10.3390/ijms241411634 -
Archivio Italiano Di Urologia,... Jan 2024Most men diagnosed with prostate cancer will be candidates for active treatment and 20 to 50% of patients treated with organ preserving strategies recur within the...
BACKGROUND
Most men diagnosed with prostate cancer will be candidates for active treatment and 20 to 50% of patients treated with organ preserving strategies recur within the prostate. Optimal treatment of recurrence is controversial. Prostate cryosurgery has been increasingly used as primary, recurrence and focal treatment for prostate cancer.
METHODS
We analysed 55 patients submitted to cryotherapy as salvage treatment after recurrence.
RESULTS
Study population presented with a mean age of 70.9 ± 6.2 years, mean initial PSA of 7.6 ng/ml and average prostate volume by ultrasound of 43.2 ± 14.7 grams. Mean follow-up was of 18.0 months. Biochemical free survival at one year of follow-up was of 85%.
CONCLUSIONS
Cryotherapy can be an effective and safe treatment for recurrence after primary curative treatment failure.
Topics: Male; Humans; Middle Aged; Aged; Cryotherapy; Prostatic Neoplasms; Prostate; Pelvis; Salvage Therapy
PubMed: 38193227
DOI: 10.4081/aiua.2023.11897 -
Scientific Reports Feb 2024According to previous observational researches and clinical trials, the gut microbiota is related to prostate diseases. However, the potential association between gut...
According to previous observational researches and clinical trials, the gut microbiota is related to prostate diseases. However, the potential association between gut microbiota and prostate disorders is still uncertain. We first identified groups of gut microbiota based on the phylum, class, order, family, and genus levels from consortium MiBioGen. And we acquired prostate diseases statistics from the FINNGEN study and PRACTICAL consortium. Next, two-sample Mendelian randomization was used to investigate the potential associations between three prevalent prostate disease and gut microbiota. In addition, we performed a reverse MR analysis and Benjamini-Hochberg (BH) test for further research. We investigated the connection between 196 gut microbiota and three prevalent prostate diseases. We identified 42 nominally significant associations and 2 robust causative links. Upon correction for multiple comparisons using the Benjamini-Hochberg procedure, our analysis revealed a positive correlation between the risk of prostatitis and the presence of the taxonomic order Gastranaerophilales. Conversely, the risk of prostate cancer exhibited an inverse correlation with the presence of the taxonomic class Alphaproteobacteria. Our study revealed the potential association between gut microbiota and prostate diseases. The results may be useful in providing new insights for further mechanistic and clinical studies of prostate diseases.
Topics: Male; Humans; Gastrointestinal Microbiome; Mendelian Randomization Analysis; Prostate; Prostatic Diseases; Prostatic Neoplasms; Alphaproteobacteria; Genome-Wide Association Study
PubMed: 38369514
DOI: 10.1038/s41598-024-54293-5