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Article
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Integrated exome and RNA sequencing of TFE3-translocation renal cell carcinoma
TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare subtype of kidney cancer with no standard treatment options for the advanced disease. Here, the authors perform genomic and transcriptomic profiling of 63 untreated primary TFE3-tRCC tumours and reveal potential therapeutic targets.
- Guangxi Sun
- , Junru Chen
- & Hao Zeng
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Article
| Open Access
Defining 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 Access
MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer
Cholesterol metabolism is involved in the progression of aggressive prostate cancer (PCa). Here the authors show that miR-205 downregulation promotes cholesterol synthesis and androgen receptor signalling in PCa through enhancing the expression of the rate-limiting enzyme of cholesterol synthesis, squalene epoxidase.
- C. Kalogirou
- , J. Linxweiler
- & A. Schulze
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Article
| Open Access
The 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 Access
An N-Cadherin 2 expressing epithelial cell subpopulation predicts response to surgery, chemotherapy and immunotherapy in bladder cancer
The identification of response biomarkers for surgery, chemotherapy and immune checkpoint therapy in bladder cancer is crucial. Here, single nuclei RNA sequencing and spatial profiling identify a cancer cell population expressing Neural Type Cadherin 2 that associates with distinct treatment outcomes.
- Kenneth H. Gouin III
- , Nathan Ing
- & Dan Theodorescu
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Matters Arising
| Open AccessReconciling differences in impact of molecular subtyping on response to cisplatin-based chemotherapy
- Mathieu Roumiguie
- , Alberto Contreras-Sanz
- & Peter C. Black
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Article
| Open Access
An 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 Access
Multiplexed 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 Access
EZH2-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 Access
The 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 Access
Subtype-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 Access
Temporal 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 Access
Role of neutrophil extracellular traps in radiation resistance of invasive bladder cancer
Radioresistance remains a challenge in the treatment of bladder cancer. In this study, the authors show in mice that radiation increases deposits of neutrophil extracellular traps (NETs) via a TLR4-dependent mechanism and that NETs-targeting strategies can improve the response to radiotherapy.
- Surashri Shinde-Jadhav
- , Jose Joao Mansure
- & Wassim Kassouf
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Article
| Open Access
An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer
Multiple molecular profiling methods are required to study urothelial non-muscle-invasive bladder cancer (NMIBC) due to its heterogeneity. Here the authors integrate multi-omics data of 834 NMIBC patients, identifying a molecular subgroup associated with multiple alterations and worse outcomes.
- Sia Viborg Lindskrog
- , Frederik Prip
- & Lars Dyrskjøt
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Article
| Open Access
Dominant role of CDKN2B/p15INK4B of 9p21.3 tumor suppressor hub in inhibition of cell-cycle and glycolysis
The human chromosome locus 9p21.3 is a tumour suppressor hub which encodes three CDK inhibitors, p15INK4B, p14ARF and p16INK4A. Here, the authors show that p15INK4B inhibits the cell cycle and glycolysis in a murine model of HRas + ‐mediated urothelial carcinoma and has a more relevant role as a tumour suppressor than its neighbouring p16INK4A.
- Yong Xia
- , Yan Liu
- & Xue-Ru Wu
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Article
| Open Access
Reprogramming 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 Access
SUMOylation 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 Access
CRISPRi 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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| Open Access
Acetylation 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 Access
Inter- 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 Access
Patient-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 Access
Plasma 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 Access
Distinct 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 Access
Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma
Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.
- Ziad Bakouny
- , David A. Braun
- & Toni K. Choueiri
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Article
| Open Access
Dual 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 Access
Mesenchymal stem cell-derived interleukin-28 drives the selection of apoptosis resistant bone metastatic prostate cancer
The effects of bone-marrow derived MSCs on prostate cancer cells remain unknown. Here the authors show that MSC-derived IL-28 induces prostate cancer cell apoptosis via IL-28Rα-STAT1 signalling, while acquired resistance to apoptosis is associated with a shift in IL-28Rα signalling via STAT1 to STAT3.
- Jeremy J. McGuire
- , Jeremy S. Frieling
- & Conor C. Lynch
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Article
| Open Access
The 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 Access
Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer
In metastatic urothelial carcinoma, it has not been established whether circulating tumor DNA (ctDNA) can replace archival primary tissue to assess mutations and biomarkers. Here, the authors show high mutation concordance between ctDNA and tumour tissue, with high consistency in serial samples.
- Gillian Vandekerkhove
- , Jean-Michel Lavoie
- & Alexander W. Wyatt
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Article
| Open Access
Tipping the immunostimulatory and inhibitory DAMP balance to harness immunogenic cell death
Most chemotherapeutic agents, including gemcitabine, do not elicit immunogenic cell death, a phenomenon associated with the release of damage-associated molecule patterns (DAMPs). Here, the authors show that gemcitabine-treated dying cancer cells express hallmark DAMPs but their immunogenic properties are hindered by the concomitant release of the inhibitory DAMP PGE2.
- K. Hayashi
- , F. Nikolos
- & K. S. Chan
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Article
| Open Access
Quantifying the influence of mutation detection on tumour subclonal reconstruction
The impact of variant calling algorithms on the analysis of intra-tumour heterogeneity has not been properly quantified. Here the authors measure the variability of 22 pipelines with different variant callers and clustering algorithms for subclonal reconstruction to inform future analyses.
- Lydia Y. Liu
- , Vinayak Bhandari
- & Paul C. Boutros
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Article
| Open Access
Common germline-somatic variant interactions in advanced urothelial cancer
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.
- Aram Vosoughi
- , Tuo Zhang
- & Bishoy M. Faltas
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Article
| Open Access
Role 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 Access
Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma
Bladder urothelial carcinoma is one of the most prevalent urogenital cancer types with limited therapeutic options. Here, the authors characterize the tumor immune microenvironment of bladder cancer using single cell RNA sequencing and suggest a role for inflammatory cancer-associated fibroblasts in tumor progression.
- Zhaohui Chen
- , Lijie Zhou
- & Ke Chen
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Article
| Open Access
Prostate 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 Access
Histone 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 Access
HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice
Genetic inactivation of VHL leads to stabilization of HIF-1α/HIF-2α and is associated with clear cell renal cell carcinoma (ccRCC) initiation and progression. Using an autochthonous mouse model of ccRCC with Vhl deletion, here the authors show that HIF-1α is necessary for tumor formation, while HIF-2α deletion has only a moderate effect.
- Rouven Hoefflin
- , Sabine Harlander
- & Ian J. Frew
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Article
| Open Access
The genomic and epigenomic evolutionary history of papillary renal cell carcinomas
Many tumours are heterogenous, which calls into question whether multiple biopsies are required to accurately assess the cancer. Here, the authors show that papillary renal cell carcinoma is clonal in nature, suggesting that in this cancer one biopsy is sufficient for diagnosis and molecular analyses.
- Bin Zhu
- , Maria Luana Poeta
- & Maria Teresa Landi
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Article
| Open Access
The 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 Access
Epithelial plasticity can generate multi-lineage phenotypes in human and murine bladder cancers
Recent studies have utilized bulk tumour mRNA sequencing to classify bladder cancers into distinct subgroups. Here, the authors use single cell transcriptomic analysis and cell transplant studies to show that epithelial plasticity can generate basal, luminal and mesenchymal phenotypes in human and murine bladder cancers.
- John P. Sfakianos
- , Jorge Daza
- & David J. Mulholland
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Article
| Open Access
2,4-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 Access
Sequential 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 Access
Effective combinatorial immunotherapy for penile squamous cell carcinoma
Penile squamous cell carcinoma (PSCC) is a cancer that is associated with significant mortality. Here, the authors develop a mouse model of PSCC by co-deletion of Smad4 and Apc in the androgen-responsive penile epithelium, and show synergistic efficacy of checkpoint therapy with cabozantinib or celecoxib in their model.
- Tianhe Huang
- , Xi Cheng
- & Xin Lu
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Article
| Open Access
Intron 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 Access
Genetic 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 Access
Prostate-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 Access
Loss 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 Access
OXPHOS 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 Access
Inhibiting WNT and NOTCH in renal cancer stem cells and the implications for human patients
Cancer stem cells are thought to be largely resistant to treatment and can be responsible for tumour recurrence. Here, using renal cancer organoids, self-renewing sphere cultures and PDX from patients, the authors show that the proliferation of stem cells within organoids, PDX and spheres can be blocked by the concomitant inhibition of the NOTCH and WNT pathways.
- Annika Fendler
- , Daniel Bauer
- & Walter Birchmeier
Single-cell ATAC and RNA sequencing reveal pre-existing and persistent cells associated with prostate cancer relapse