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| Open AccessThe long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer
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.
- Neha Singh
- , Varune R. Ramnarine
- & Andrew S. Kraft
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Article
| Open AccessDynamic prostate cancer transcriptome analysis delineates the trajectory to disease progression
Transcriptional changes during prostate cancer progression are not yet fully understood. Here, the authors integrate a transcriptomics atlas of prostate cancer and validate it with preclinical models and single-cell RNA-seq, revealing the role of EZH2 and macrophage polarisation in tumour progression.
- Marco Bolis
- , Daniela Bossi
- & Jean-Philippe P. Theurillat
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Article
| Open AccessThe telomere length landscape of prostate cancer
Despite the known role of telomere length in cancer, its association with genomic features remains unclear. Here, the authors integrate telomere length, genomics, transcriptomics and proteomics in localized prostate cancer and reveal links between telomere maintenance, disease drivers and clinical outcomes.
- Julie Livingstone
- , Yu-Jia Shiah
- & Paul C. Boutros
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Article
| Open AccessG3BP1 inhibits Cul3SPOP to amplify AR signaling and promote prostate cancer
SPOP functions as a tumour suppressor in prostate cancer but how the protein is regulated is unclear. Here, the authors identify G3BP1 as a competitive inhibitor of SPOP and show that G3BP1-SPOP axis activates androgen signalling to drive tumorigenesis.
- Chandrani Mukhopadhyay
- , Chenyi Yang
- & Pengbo Zhou
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Article
| Open AccessOpposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer
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.
- Meixia Che
- , Aashi Chaturvedi
- & Scott M. Dehm
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Article
| Open AccessSomatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse
Biomarkers of prostate cancer metastasis have been difficult to determine with confidence. Here the authors analyse mutation prevalence in 1844 prostate cancers and show that ZNRF3 loss is enriched in metastatic, castration-resistant prostate cancer and associated with metastasis of localized disease.
- Michael Fraser
- , Julie Livingstone
- & Paul C. Boutros
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Article
| Open AccessSPOP mutation induces DNA methylation via stabilizing GLP/G9a
The molecular mechanism underlying the DNA hypermethylation phenotype observed in the SPOP-mutant prostate cancers is unclear. Here, the authors show that mutant SPOP induces global aberrant DNA methylation patterns through GLP/G9a and renders prostate cancer cells susceptible to DNA demethylating agents.
- Jianong Zhang
- , Kun Gao
- & Haojie Huang
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Comment
| Open AccessBreaking down walls in prostate cancer with the MURAL collection of patient-derived xenografts
A bank of 59 well-characterised prostate cancer patient-derived xenografts was established, including 17 classed as research-ready covering the disease-spectrum which, plus associated resources (organoids, serum, DNA/RNA profiles, tissue), are available for collaborative projects. This eagerly-anticipated resource will facilitate pre-clinical prostate cancer therapy studies.
- Charlotte L. Bevan
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Article
| Open AccessA prostate-specific membrane antigen activated molecular rotor for real-time fluorescence imaging
Detection of the tumour boundary in prostate cancer is required for surgery. Here the authors present a fluorescent molecular rotor probe to target a prostate cancer marker, prostate-specific membrane antigen (PSMA), which they use in a xenograft mouse model to show it can be used for in vivo imaging.
- Jingming Zhang
- , Anastasia Rakhimbekova
- & Xing Yang
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Article
| Open AccessTranscriptional network involving ERG and AR orchestrates Distal-less homeobox-1 mediated prostate cancer progression
Distal-less homeobox 1 (DLX1) is reported as a prostate cancer (PCa) diagnostic biomarker, but the mechanism for its upregulation in PCa is unclear. Here the authors show that ERG, AR and FOXA1 transcriptionally regulates DLX1 expression in PCa, and the inhibition of this ERG/AR transcriptional circuitry with a BET inhibitor reduces the oncogenic effects of DLX1.
- Sakshi Goel
- , Vipul Bhatia
- & Bushra Ateeq
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Article
| Open AccessSingle-cell ATAC and RNA sequencing reveal pre-existing and persistent cells associated with prostate cancer relapse
Identifying the molecular mechanisms of response to systemic therapy in prostate cancer remains crucial. Here, the authors apply single cell-ATAC and RNAseq to models of early treatment response and resistance to enzalutamide and identify chromatin and gene expression patterns that can predict treatment response.
- S. Taavitsainen
- , N. Engedal
- & A. Urbanucci
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Article
| Open AccessDefining the therapeutic selective dependencies for distinct subtypes of PI3K pathway-altered prostate cancers
Understanding the mechanisms driving PI3K isoform dependency in prostate cancer can help the design of future clinical trials. Here, the authors show that gain-of-function mutations in PIK3CA or PIK3CB can confer PI3K p110 isoform dependency and that the direct inhibition of AKT may be superior to PI3K inhibition in PTEN-deficient prostate cancers.
- Ninghui Mao
- , Zeda Zhang
- & Brett S. Carver
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Article
| Open AccessThe MURAL collection of prostate cancer patient-derived xenografts enables discovery through preclinical models of uro-oncology
The prognosis of castration-resistant prostate cancers remains dismal, but accurate preclinical models can lead to effective therapies. Here the Melbourne Urological Research Alliance establish prostate cancer patient-derived xenografts, use the tumors for organoids and single-cell RNA-seq, and show the efficacy of PARP inhibitor combination treatments.
- Gail P. Risbridger
- , Ashlee K. Clark
- & Renea A. Taylor
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Article
| Open AccessAn integrated functional and clinical genomics approach reveals genes driving aggressive metastatic prostate cancer
It is hypothesized that there are a number of tumor specific driver genes for metastatic prostate cancer. Here, the authors perform genome-wide CRISPRi screens and integrate these data with metastatic prostate cancer functional and clinical genomics data to show that KIF4A and WDR62 drive aggressive prostate cancer phenotypes.
- Rajdeep Das
- , Martin Sjöström
- & Luke A. Gilbert
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Article
| Open AccessMultiplexed functional genomic analysis of 5’ untranslated region mutations across the spectrum of prostate cancer
Mutations in 5’ untranslated regions (UTRs) have a functional role in gene expression in cancer. Here, the authors develop a sequencing-based high throughput functional assay named PLUMAGE and show the effects of these mutations on gene expression and their association with clinical outcomes in prostate cancer.
- Yiting Lim
- , Sonali Arora
- & Andrew C. Hsieh
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Article
| Open AccessEZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer
Although the TMPRSS2-ERG gene fusion is the most common alteration in human prostate cancer, its involvement in disease progression remains unclear. Here, the authors demonstrate that ERG is methylated by Enhancer of zest homolog 2 leading to enhanced transcriptional and oncogenic activity.
- Marita Zoma
- , Laura Curti
- & Giuseppina M. Carbone
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Article
| Open AccessThe antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells
TMPRSS2 is regulated by androgen receptor signalling in the prostate, however it is unclear if blocking this signalling is beneficial in the context of SARS-CoV-2 lung infection. Here the authors show that antiandrogen treatment downregulates TMPRSS2 in the lung and reduces viral entry and infection.
- D. A. Leach
- , A. Mohr
- & G. N. Brooke
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Article
| Open AccessSubtype-specific collaborative transcription factor networks are promoted by OCT4 in the progression of prostate cancer
Transcription factors (TFs) often form distinct networks to regulate transcriptional program during cancer progression. Here the authors show that OCT4 is a common transcriptional factor in two types of advanced PC and as such, OCT4 accelerates a TF complex formation with the FOXA1/AR in castration-resistant PC and NRF1 in neuroendocrine PC.
- Ken-ichi Takayama
- , Takeo Kosaka
- & Satoshi Inoue
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Article
| Open AccessTemporal evolution of cellular heterogeneity during the progression to advanced AR-negative prostate cancer
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.
- Nicholas J. Brady
- , Alyssa M. Bagadion
- & David S. Rickman
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Article
| Open AccessReprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer
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.
- Sylvan C. Baca
- , David Y. Takeda
- & Matthew L. Freedman
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Article
| Open AccessSUMOylation controls the binding of hexokinase 2 to mitochondria and protects against prostate cancer tumorigenesis
The oncogenic activity of Hexokinase 2, the first rate-limiting enzyme of glycolysis, requires its mitochondrial localization. Here, the authors show that SUMOylation of hexokinase 2 disrupts its binding to mitochondria and protects cells from tumorigenesis in prostate cancer.
- Xun Shangguan
- , Jianli He
- & Wei Xue
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Article
| Open AccessCRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer
Prostate cancer risk-associated SNPs are enriched in noncoding CREs. Here the authors perform CRISPRi screens of CREs in prostate cancer cell lines to describe a causal mechanism synergistically driven by a risk SNP and DNA methylation-mediated 3D genome architecture.
- Musaddeque Ahmed
- , Fraser Soares
- & Housheng Hansen He
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Article
| Open AccessAcetylation of KLF5 maintains EMT and tumorigenicity to cause chemoresistant bone metastasis in prostate cancer
The therapies for bone metastatic prostate cancer are limited and the underlying mechanisms are unclear. Here, the authors show that bone derived TGF-β induces acetylation of KLF5 (Ac-KLF5), and Ac-KLF5 promotes prostate cancer bone metastasis and resistance to docetaxel by upregulating CXCR4.
- Baotong Zhang
- , Yixiang Li
- & Jin-Tang Dong
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Article
| Open AccessInter- and intra-tumor heterogeneity of metastatic prostate cancer determined by digital spatial gene expression profiling
The inter- and intra-tumor heterogeneity of metastatic prostate cancer (mPC) is underexplored. Here the authors use Digital Spatial Profiling to study gene and protein expression heterogeneity in 27 mPC patients, finding variation in associated pathways and potential immunotherapy targets.
- Lauren Brady
- , Michelle Kriner
- & Peter S. Nelson
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Article
| Open AccessPatient-derived xenografts and organoids model therapy response in prostate cancer
To date, patients still succumb to cancer, due to tumors not responding to therapy or ultimately acquiring resistance. Here the authors show that by exploiting patient derived organoids and a treatment-naïve patient derived xenograft, patient therapy can be personalized.
- Sofia Karkampouna
- , Federico La Manna
- & Marianna Kruithof-de Julio
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Article
| Open AccessPlasma cells are enriched in localized prostate cancer in Black men and are associated with improved outcomes
A recent report suggested Black men with prostate cancer were more responsive to immunotherapy. Here, the authors analysed prostate cancer gene expression profiles and show tumours from Black men and men with African ancestry have an increased proportion of plasma cells compared to those of White men and this correlates with improved outcome following treatment.
- Adam B. Weiner
- , Thiago Vidotto
- & Edward M. Schaeffer
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Article
| Open AccessDistinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide
Enzalutamide, an approved drug for prostate cancer, acts on TMPRSS2 expression, a key mediator for SARS-CoV-2 infection. Here, the authors characterize the anti-SARS-CoV-2 effects of Enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and in hACE2-transduced Tmprss2 knockout mice and show lack antiviral action in human lung cells and human lung organoids, likely due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells.
- Fei Li
- , Ming Han
- & Dong Gao
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Article
| Open AccessDual functions of SPOP and ERG dictate androgen therapy responses in prostate cancer
Gene fusions involving the ERG transcription factor and point mutations in the ubiquitin ligase adaptor SPOP are two truncal mutations that are mutually exclusively present in prostate cancer. Here, the authors show that mutations in SPOP render prostate tumor cells sensitive to antiandrogen therapy and that the presence of ERG promotes sensitivity to high dose of androgen and SPOP inhibition.
- Tiziano Bernasocchi
- , Geniver El Tekle
- & Jean-Philippe P. Theurillat
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Article
| Open AccessThe circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair
Cryptochrome 1 (CRY1) is a transcriptional coregulator associated with the circadian clock. Here the authors reveal that CRY1 is hormone-regulated, stabilized by genomic insult, and promotes DNA repair and cell survival through temporal transcriptional regulation.
- Ayesha A. Shafi
- , Chris M. McNair
- & Karen E. Knudsen
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Matters Arising
| Open AccessOn the reporting and analysis of a cancer evolutionary adaptive dosing trial
- Hitesh B. Mistry
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Article
| Open AccessRole of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity
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.
- Joanna Cyrta
- , Anke Augspach
- & Mark A. Rubin
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Article
| Open AccessProstate cancer evolution from multilineage primary to single lineage metastases with implications for liquid biopsy
The evolutionary progression from primary to metastatic prostate cancer is largely uncharted, and the implications for liquid biopsy are unexplored. Here, the authors use deep genomic sequencing and histopathological information to trace tumor evolution both within the prostate and during metastasis in ten men.
- D. J. Woodcock
- , E. Riabchenko
- & D. C. Wedge
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Article
| Open AccessHistone methyltransferase DOT1L coordinates AR and MYC stability in prostate cancer
Histone methyltransferase, DOTL1 is implicated in the pathogenesis of MLL-rearranged leukemia, however, not much is known of its role in prostate cancer (PCa). Here, the authors report that DOTL1 inhibition suppresses both androgen receptor and MYC pathways in a negative feed forward manner to reduce growth of AR-positive PCa.
- R. Vatapalli
- , V. Sagar
- & S. A. Abdulkadir
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Article
| Open AccessThe MAO inhibitors phenelzine and clorgyline revert enzalutamide resistance in castration resistant prostate cancer
Castration resistant prostate cancer patients treated with enzalutamide may develop resistance to the drug. Here, the authors report that monoamine oxidase-A expression is increased in these resistant tumors and that the antidepressants phenelzine/clorgyline can reverse such resistance to further suppress tumor growth
- Keliang Wang
- , Jie Luo
- & Chawnshang Chang
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Article
| Open Access2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer
Androgen receptor (AR) signalling regulates cellular metabolism in prostate cancer. Here, the authors perform a proteomics and metabolomics characterisation of prostate cancer cells adapted to long-term resistance to AR inhibition and show rewiring of glucose and lipid metabolism, and further identify a signature associated with resistance to AR inhibition.
- Arnaud Blomme
- , Catriona A. Ford
- & Hing Y. Leung
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Article
| Open AccessSequential Ras/MAPK and PI3K/AKT/mTOR pathways recruitment drives basal extrusion in the prostate-like gland of Drosophila
The molecular mechanisms leading to basal extrusion are unclear. Here, the authors use the Drosophila accessory gland to model human prostate acini and show that Ras/MAPK and PI3K/AKT/mTOR pathways are co-activated in two autocrine loops by dEGF and dIGF, inducing basal extrusion and subsequent tumour formation.
- Amandine Rambur
- , Corinne Lours-Calet
- & Cyrille de Joussineau
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Article
| Open AccessIntron retention is a hallmark and spliceosome represents a therapeutic vulnerability in aggressive prostate cancer
Dysregulation of mRNA alternative splicing is prevalent in cancers. Here, the authors characterized the landscape of aberrant alternative splicing during the development of prostate cancer, progression and therapeutic resistance and show that splicing modulator, E7107, reduces growth in castration-resistant prostate cancer.
- Dingxiao Zhang
- , Qiang Hu
- & Dean G. Tang
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Article
| Open AccessGenetic characterization of a unique neuroendocrine transdifferentiation prostate circulating tumor cell-derived eXplant model
Better tumor models are needed for the neuroendocrine subtype of castration resistant prostate cancer (CRPC-NE). Here, the authors develop patient-derived model from circulating tumor cells of a CRPC-NE patient, and provide insights on the sequential acquisition of driver gene mutations promoting NE transdifferentiation.
- Vincent Faugeroux
- , Emma Pailler
- & Françoise Farace
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Article
| Open AccessProstate-specific antigen dynamics predict individual responses to intermittent androgen deprivation
Prostate specific antigen (PSA) is a biomarker for prostate cancer. Here, the authors develop a mathematical model where longitudinal changes in PSA levels predict responses to intermittent androgen deprivation in patients with prostate cancer.
- Renee Brady-Nicholls
- , John D. Nagy
- & Heiko Enderling
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Article
| Open AccessLoss of testosterone impairs anti-tumor neutrophil function
It is known that there are sex differences in the incidence and prognosis of certain cancers, including melanoma. In this study, the authors utilize a melanoma model to reveal that castrated mice have a higher metastatic burden associated with androgen dependent impaired neutrophil function.
- Janet L. Markman
- , Rebecca A. Porritt
- & Moshe Arditi
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Article
| Open AccessOXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation
The re-wiring of the metabolic machinery is a common feature in cancer. Here, the authors show, using paired normal and prostate cancer samples that the cancer samples exhibit a shift to succinate respiration, which is associated with elevated levels of mitochondrial DNA mutations.
- Bernd Schöpf
- , Hansi Weissensteiner
- & Helmut Klocker
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Article
| Open AccessA case report of multiple primary prostate tumors with differential drug sensitivity
Prostate cancer is often a multifocal disease but how best to manage this clinically remains unclear. Here, the authors report a single case study of a patient with two genetically diverse tumours which showed differential response to therapy.
- Scott Wilkinson
- , Stephanie A. Harmon
- & Adam G. Sowalsky
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Article
| Open AccessAndrogen receptor-binding sites are highly mutated in prostate cancer
Androgen receptor (AR) mediated transcription is critical to prostate tumorigenesis and development. Here, utilising clinical whole genome sequencing data, the authors show that the non-coding AR binding sites on DNA are frequently mutated in prostate cancer potentially due to faulty base excision repair mechanisms
- Tunç Morova
- , Daniel R. McNeill
- & Nathan A. Lack
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Article
| Open AccessAndrogen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in 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.
- Ritika Tiwari
- , Nishat Manzar
- & Bushra Ateeq
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Article
| Open AccessMUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer
MUC1-C is overexpressed in castration-resistant prostate cancer and neuroendocrine prostate cancer. Here, the authors show that MUC1-C drives lineage plasticity through MYC and BRN2, inducing neuroendocrine features and stemness in prostate cancer.
- Yota Yasumizu
- , Hasan Rajabi
- & Donald Kufe
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Article
| Open AccessLRIG1 is a pleiotropic androgen receptor-regulated feedback tumor suppressor in prostate cancer
LRIG1 is a tumour suppressor in several cancers. Here, the authors show that androgen receptor directly transactivates LRIG1 which then antagonises ERBB signalling and c-Myc expression to inhibit prostate tumorigenesis.
- Qiuhui Li
- , Bigang Liu
- & Dean G. Tang
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Article
| Open AccessThe genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact
Detecting genomic abnormalities in metastatic castration-resistant prostate cancer (mCRPC) may impact clinical treatment. Here, the authors present whole-genome sequencing of metastatic biopsies from 197 mCRPC patients, highlighting the landscape of microsatellite stability, homologous repair deficiency, and other genomic subgroups.
- Lisanne F. van Dessel
- , Job van Riet
- & Martijn P. Lolkema
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Article
| Open AccessHigh-fat diet fuels prostate cancer progression by rewiring the metabolome and amplifying the MYC program
Prostate cancer progression may be enhanced by a high-fat diet. Here the authors show that a diet high in saturated fats enhance the MYC-driven transcriptional program, a feature that independently predicts prostate cancer progression and death.
- David P. Labbé
- , Giorgia Zadra
- & Myles Brown
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Article
| Open AccessIdentification of the PTEN-ARID4B-PI3K pathway reveals the dependency on ARID4B by PTEN-deficient prostate cancer
The identification of synthetic essential genes of PTEN is of therapeutic potential for PTEN-deficient prostate cancers. Here, the authors show that ARID4B is a synthetic essential gene in these cancers in which deficiency of PTEN prompts the AKT-ARID4B feedback loop required for activation of the PI3K-AKT signaling pathway.
- Ray-Chang Wu
- , In-Chi Young
- & Mei-Yi Wu