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In this study, the authors identify a collaboration between the epigenetic regulators, EZH2 and DNA methyltransferase that contributes to prostate cancer lineage reprogramming.

Elevated expression of long noncoding RNA H19 is seen in clinical samples of neuroendocrine prostate cancer (PCa). Here the authors show H19 promotes plasticity from luminal to neuroendocrine by epigenetic reprogramming.

The functional significance of the observed heterogeneity of androgen receptor (AR) expression in prostate cancer is unknown. Here the authors show AR expression heterogeneity is associated with distinct castration/enzalutamide responses and identify BCL-2 as a potential therapeutic target in castration-resistant prostate cancer.

The transition of androgen receptor-dependent prostate cancer to a therapy resistant cancer with neuroendocrine phenotype is an important process that remains poorly understood. Here, the authors show that PKCλ/ι-loss promotes epigenetic reprogramming resulting in a TGFβ resistance programme via transcriptional upregulation of translational machinery.

The epigenetic mechanisms underlying phenotypic diversity across different metastatic sites in castration-resistant prostate cancer (CRPC) remain to be characterised. Here, multi-omic profiling across metastatic lesions identifies regulatory networks driving tumour lineage programs and potential therapeutic targets.

Beltran and colleagues examine the underlying mechanisms behind the observed heterogeneous expression of the prostate cancer drug target and biomarker, PSMA, in castration-resistant prostate cancer, involving regulatory roles of both HOXB13 and AR.

Neuroendocrine prostate cancer (NEPC) is characterized by loss of androgen receptor (AR) signaling during neuroendocrine transdifferentiation, resulting in resistance to AR-targeted therapy. Here they report ONECUT2 to drive NEPC tumorigenesis via regulation of hypoxia signaling and tumor hypoxia, and find hypoxia directed therapy to be effective in NEPC.

2016 was an important year for prostate cancer research. New clinical data highlight the need for personalized treatment across clinical disease states and have changed clinical practice for men with metastatic disease. Molecular studies have characterized tumour heterogeneity and informed biomarker development for advanced disease and research into mechanisms of treatment resistance.

There are few available models to study neuroendocrine prostate cancer. Here they develop and characterize patient derived organoids from metastatic lesions, use these models to show the role of EZH2 in driving neuroendocrine phenotype, and perform high throughput organoid screening to identify therapeutic drug combinations.

Davies et al. demonstrate that androgen receptor–targeted therapy induces lineage-plastic transcriptional reprogramming, which is mediated by EZH2 and favours stem cell and neuronal gene networks in treatment-resistant prostate cancer.

SPINK1 upregulation is found in ~10–25% of prostate cancers. Here, they show that whilst SPINK1 is transcriptionally repressed by androgen receptor and its co-repressor REST, it is upregulated after androgen-deprivation therapy, which leads to neuroendocrine differentiation of prostate cancer cells.

Advances in molecular profiling technologies that capture both genotype and phenotype, coupled with an improved understanding of the biological mechanisms underlying prostate cancer progression, set new molecular biomarkers for advancement into the clinic to improve prognostication, therapy selection and disease monitoring for patients with prostate cancer.

Enhancer of zeste homolog 2 (EZH2) has been implicated as a driver of disease progression and resistance to hormonal therapies. Here, the authors focus on EZH2 in two subtypes of advanced prostate cancer and report how it modulates the bivalent genes thereby leading to forward differentiation after being targeted in neuroendocrine prostate cancer.

Inhibition of the histone methyltransferase NSD2 and the androgen receptor in preclinical models can reverse lineage plasticity to suppress tumour growth and promote cell death in multiple subtypes of castration-resistant prostate cancer.

Neuroendocrine carcinomas (NECs) arise from different anatomic sites, but have similar histological and clinical features. Here, the authors show that the epigenetic landscape of a range of NECs converges towards a common epigenetic state, while distinct subtypes occur within neuroendocrine prostate cancer contributing to intratumor heterogeneity in clinical samples.

cfDNA fragmentomics is a potential clinically applicable method for identifying cancer. Here, the authors assess fragmentomics analysis methods and their application to commercial targeted sequencing panels.

Lineage plasticity and epigenetic changes underlie prostate development and cancer evolution. A new study shows that basal and luminal prostate cells have distinct metabolic profiles, with a basal-to-luminal shift intensifying pyruvate oxidation. Metabolic changes in turn influence chromatin architecture, lineage reprogramming and treatment sensitivity.

The differentiation of prostate adenocarcinoma to neuroendocrine prostate cancer (CRPC-NE) is a mechanism of resistance to androgen deprivation therapy. Here the authors show that SWI/SNF chromatin-remodeling complex is deregulated in CRPC-NE and that the complex interacts with different lineage specific factors throughout prostate cancer transdifferentiation.

A newly published study used whole-genome sequencing of multiple prostate tumour foci from several patients with intermediate-risk prostate cancer to track evolutionary patterns and delineate the marked intrapatient molecular heterogeneity of this disease. Their findings have potential implications for the development of clinical prognostic and predictive biomarkers.

The role of germline variation in human cancers is not fully understood. Here, the authors define the landscape of putative deleterious germline variants that abrogate tumor suppressor proteins in advanced urothelial cancer patients.

Mark Rubin, Francesca Demichelis and colleagues study the evolution of urothelial carcinomas by performing whole-exome sequencing of tumors collected from patients before and after chemotherapy. They find marked within-patient tumor heterogeneity and increased mutations involved in integrin signaling pathways and APOBEC-induced mutation signatures after treatment.

While BH3-mimetics can be effective for treatment of haematological malignancies, their efficacy in solid tumours is limited. Here, using a range of patient-derived prostate cancer models, the authors demonstrate that increased replication stress induced by RB1 loss confers sensitivity to BH3 mimetics targeting BCL-XL.

This review explores the basic biology of prostate-specific membrane antigen (PSMA) and its growing significance in molecular imaging and treatment. It emphasizes the importance of understanding PSMA regulation and heterogeneity for the effective application of PSMA-targeted radioligand therapy.

This Review provides an overview of the main targetable surface proteins in prostate cancer, defined as the surfaceome, discussing the mechanisms of action and efficacy of currently available drugs targeting surface proteins, as well as future perspectives of integrating these treatments into prostate-cancer management.

Liquid biopsy assays are important to prognosticate outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients treated with androgen receptor (AR) inhibitors. Here this group reports detecting circulating tumor DNA in limiting plasma cell-free DNA of mCRPC patients as prognostic marker of poor survival after AR treatment.

Beltran and colleagues discuss the challenges in treating metastatic prostate cancer and strategies to accelerate precision oncology and improve therapy and clinical decisions in this setting.

Metastatic castration-resistant prostate cancer is treated with the microtubule-stabilizing drugs taxanes, but resistance ultimately develops. Here Galletti et al.show that ERG, a transcription factor commonly overexpressed in prostate cancers, confers taxane resistance by binding to soluble tubulin.

The molecular processes that lead to neuroendocrine prostate cancer after treating prostate adenocarcinoma (PRAD) are not well understood. Here the authors show that regulation by FOXA1 and changes in the epigenomic profile drive the transition from PRAD to a neuroendocrine phenotype.

Upper tract urothelial carcinoma (UTUC) is an aggressive cancer and largely uncharacterised cancer. Here, Faltas and colleagues report its distinctive molecular and immune landscape compared to urothelial carcinoma of the bladder and explore the role of FGFR3 signaling in UTUC biology.

While many treatments for prostate cancer suppress the androgen receptor it becomes reactivated during disease progression. Here, the authors show that a KLF5 transcriptional programme is also activated during treatment and promotes migration and the appearance of a basal cell phenotype.

The heterogeneity of tumor evolution from AR-positive, adenocarcinoma to AR-negative, neuroendocrine prostate cancer (NEPC) is not fully characterized. Here the authors generate a mouse model to show that Rb1 loss and MYCN overexpression accelerates the progression to AR-negative NEPC and identify emergence of distinct subpopulations of NEPC cells.

Genome-wide DNA methylation analysis of metastatic biopsies from patients with castration-resistant prostate cancer reveals marked epigenetic differences between samples with adenocarcinoma and neuroendocrine histologies.

While prostate cancer predominantly exhibits androgen dependence, oestrogen receptor (ER) signalling is also involved. Here, Chakravarty et al.show that ERα regulates the expression of the NEAT1 long non-coding RNA, which in turn promotes tumorigenesis by maintaining an oncogenic programme/cascade.

Clinical tests that rely on next-generation sequencing to evaluate large numbers of cancer genes can be validated using pooled cell lines with known mutations.

A number of targetable molecular alterations and resistance mechanisms have been identified in metastatic castration-resistant prostate cancer (mCRPC). As our understanding of the genomic landscape of mCRPC increases, biomarker-driven clinical trials investigating targeted therapies will enable an increasingly personalized approach to its treatment.

Ada Gjyrezi et al. show that ddPCR can be used to accurately measure androgen receptor variant (AR-V) expression levels in single circulating tumor cells (CTCs) from prostate cancer patients. They show that current methods for isolating CTCs tend to underestimate the prevalence of AR-V and that a specific variant, AR-v567es, could be potentially used as a biomarker for an aggressive subtype of prostate cancer.

Single-cell transcriptomic analysis of metastatic castration-resistant prostate cancer uncovers pervasive coexpression of androgen receptor isoforms and cancer cell–intrinsic and microenvironmental programs of treatment resistance

Glucose–insulin feedback can reactivate PI3K in tumours treated with PI3K inhibitors, reducing therapeutic efficacy, but this effect can be reduced by using drugs or diet to suppress the insulin response.

Meta-analysis of exome sequencing data identifies new recurrently mutated driver genes for prostate cancer. Comparison of primary and metastatic tumors further identifies genomic markers for advanced prostate cancer that may inform risk stratification.

Genetically engineered colon organoids form tumors that undergo a stepwise progression toward metastatic disease after orthotopic transplantation.