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| Open AccessProteogenomic characterization of MiT family translocation renal cell carcinoma
The molecular landscape of microphthalmia transcription factor family translocation renal cell carcinoma tumours remain to be characterised. Here, the authors perform proteogenomic analysis and reveal dysregulation of DNA repair, mTOR signalling and metabolic processes.
- Yuanyuan Qu
- , Xiaohui Wu
- & Chen Ding
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Article
| Open AccessExtensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential
Epigenetic reprogramming of the androgen receptor (AR) has been identified as an important process driving prostate cancer (PCa) progression. Here, the authors analyze the role of AR chromatin binding heterogeneity in PCa clinical outcomes, metastasis and relapse.
- Jeroen Kneppers
- , Tesa M. Severson
- & Wilbert Zwart
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Article
| Open AccessExtensive germline-somatic interplay contributes to prostate cancer progression through HNF1B co-option of TMPRSS2-ERG
The role of risk loci identified from genome-wide association studies in prostate cancer (PCa) progression remains poorly characterised. Here, the authors report enrichment of transcription factor genes within PCa risk-associated regions and germline-somatic interaction between TMPRSS2-ERG fusion and genetic variations.
- Nikolaos Giannareas
- , Qin Zhang
- & Gong-Hong Wei
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Article
| Open AccessARID1A loss induces polymorphonuclear myeloid-derived suppressor cell chemotaxis and promotes prostate cancer progression
The accumulation of myeloid derived suppressor cells (MDSC) has been associated with prostate cancer progression and castration resistance. Here the authors show that loss of ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, results in polymorphonuclear-MDSC infiltration and cooperates with Pten loss to accelerate prostate tumorigenesis.
- Ni Li
- , Qiuli Liu
- & Jun Qin
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Article
| Open AccessInhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance
Immune checkpoint blockade is showing promise in cancer immune therapy, but many solid tumours are resistant. Authors here identify a pathway in T cells that leads to increased activity of C-terminal Src kinase, a negative regulator of T cell activity, thus disabling tumour infiltrating T cells and causing immune therapy resistance.
- Dhivya Sridaran
- , Surbhi Chouhan
- & Nupam P. Mahajan
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Article
| Open AccessAn mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss
The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1. Here, authors demonstrate that TFEB is paradoxically hypophosphorylated and activated in cells with TSC2 loss due to impaired lysosomal recruitment of the FLCN:FNIP2 complex in renal cells.
- Kaushal Asrani
- , Juhyung Woo
- & Tamara L. Lotan
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Article
| Open AccessSingle cell sequencing reveals that CD39 inhibition mediates changes to the tumor microenvironment
The molecular mechanisms underlying tumour heterogeneity in bladder cancer remain to be explored. Here, the authors perform single cell RNA sequencing and identify CD39 as a potential target for immunotherapy, which they validate in vivo.
- Lilong Liu
- , Yaxin Hou
- & Ke Chen
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Article
| Open AccessCollaborative study from the Bladder Cancer Advocacy Network for the genomic analysis of metastatic urothelial cancer
The Bladder Cancer Advocacy Network established the UC-GENOME study in order to create a biobank and data repository for metastatic urothelial carcinoma. Here, the authors present the first characterization and analysis of DNA and RNA sequencing data from the 218 patients included in the UC-GENOME.
- Jeffrey S. Damrauer
- , Wolfgang Beckabir
- & Matthew I. Milowsky
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Article
| Open AccessFOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation
Bladder cancer can often exhibit genomic and morphological heterogeneity. Here, the authors use genomics analysis to show lineage plasticity of bladder cancers with squamous differentiation, and identify key transcription factors related to this morphological and immune heterogeneity.
- Joshua I. Warrick
- , Wenhuo Hu
- & Hikmat A. Al-Ahmadie
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Article
| Open AccessStromal androgen signaling acts as tumor niches to drive prostatic basal epithelial progenitor-initiated oncogenesis
Prostate stromal cells can contribute to prostate tumorigenesis. Here the authors show that the loss of androgen receptor signalling in Gli1-lineage stromal cells diminishes prostate epithelial oncogenic transformation and tumor growth in mouse models and this is due to insulin-like growth factor binding protein 3-mediated inhibiting IGF1 and Wnt/β-catenin signalling activation.
- Alex Hiroto
- , Won Kyung Kim
- & Zijie Sun
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Article
| Open AccessThe cell-free DNA methylome captures distinctions between localized and metastatic prostate tumors
Metastatic prostate cancer can be difficult to biopsy and characterise. Here, the authors use cell-free DNA methylation analysis to illustrate changes in hypermethylation in metastatic disease.
- Sujun Chen
- , Jessica Petricca
- & Housheng Hansen He
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Article
| Open AccessRetinoblastoma protein as an intrinsic BRD4 inhibitor modulates small molecule BET inhibitor sensitivity in cancer
Here the authors identify retinoblastoma (RB) protein as an intrinsic inhibitor of BRD4 and demonstrate that loss of RB induces BRD4 cistrome changes in the genome and enrichment of GPCR-cAMP signaling pathway, conferring resistance to small molecule BET inhibitor.
- Donglin Ding
- , Rongbin Zheng
- & Haojie Huang
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Article
| Open AccessSingle cell analysis of cribriform prostate cancer reveals cell intrinsic and tumor microenvironmental pathways of aggressive disease
The molecular and cellular underpinnings of cribriform prostate cancer aggressiveness remain to be explored. Here, the authors perform single-cell RNA-sequencing, TCR sequencing and histology and reveal cancer cell intrinsic pathways and an immunosuppressive tumour microenvironment.
- Hong Yuen Wong
- , Quanhu Sheng
- & Paula J. Hurley
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Article
| Open AccessMolecular characterization of renal cell carcinoma tumors from a phase III anti-angiogenic adjuvant therapy trial
Based on the S-TRAC results, sunitinib is approved as adjuvant treatment for adult patients at high risk of recurrent RCC following nephrectomy. Here, the authors report the results of an integrated multi-omics tumor analysis of 171 patients from the trial and identify specific molecular subtypes as well as potential new targets.
- Robert J. Motzer
- , Jean-François Martini
- & Alain Ravaud
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Article
| Open AccessA transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma
Metastatic clear cell renal cell carcinoma has a poor prognosis. Here, the authors use single cell RNA-seq to show a distinct gene expression signature in the primary tumour of metastatic patients, and highlights immune cell receptor interactions as potential therapeutic targets.
- Adele M. Alchahin
- , Shenglin Mei
- & Ninib Baryawno
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Article
| Open AccessSpatio-temporal analysis of prostate tumors in situ suggests pre-existence of treatment-resistant clones
Spatial heterogeneity in prostate cancer can contribute to its resistance to androgen deprivation therapy (ADT). Here, the authors analyse prostate cancer samples before and after ADT using Spatial Transcriptomics, and find heterogeneous pre-treatment tumour cell populations and stromal cells that are associated with resistance.
- Maja Marklund
- , Niklas Schultz
- & Joakim Lundeberg
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Article
| Open AccessTranscriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity
Lineage plasticity is increasingly recognized as an emergent resistance mechanism after treatment with androgen receptor signalling inhibitors. To understand determinants of resistance, the authors analyzed the transcriptomes of patient tumor biopsies before enzalutamide treatment and at progression and identified a gene expression program associated with lineage plasticity risk and poor outcomes.
- Thomas C. Westbrook
- , Xiangnan Guan
- & Joshi J. Alumkal
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Article
| Open AccessReformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer
Chondroitin sulfate (CS) is one of the most abundant glycosaminoglycans in prostate cancers. Here the authors show that inhibition of the androgen receptor pathway leads to the upregulation of CS, which promotes prostate cancer growth and metastasis.
- Nader Al-Nakouzi
- , Chris Kedong Wang
- & Mads Daugaard
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Article
| Open AccessTargeting the Retinoblastoma/E2F repressive complex by CDK4/6 inhibitors amplifies oncolytic potency of an oncolytic adenovirus
Neither CDK4/6 inhibitors nor oncolytic adenoviruses show high efficiency as monotherapy in the treatment of cancer. Authors show here that when combined, CDK4/6 inhibitors deplete Retinoblastoma protein levels, which leads to more efficient virus replication and an increase in oncolytic virus-producing cancer cells and thus to efficient anti-tumor response in mouse xenograft sarcoma models.
- Jana Koch
- , Sebastian J. Schober
- & Per Sonne Holm
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Article
| Open AccessAberrant androgen action in prostatic progenitor cells induces oncogenesis and tumor development through IGF1 and Wnt axes
Activation of the androgen receptor (AR) through androgen binding is essential for prostate tumorigenesis. Here the authors show that AR activation in a subpopulation of prostatic progenitor cells can initiate prostatic intraepithelial neoplasia formation and promotes prostate cancer development through activation of IGF1 and Wnt/β-catenin signalling pathways.
- Won Kyung Kim
- , Adam W. Olson
- & Zijie Sun
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Article
| Open AccessLysosomal protein transmembrane 5 promotes lung-specific metastasis by regulating BMPR1A lysosomal degradation
The mechanisms that confer lung-specific metastasis in renal cell carcinomas (RCC) remain to be detailed. Here the authors show that LAPTM5 contributes to lung-specific metastasis of RCCs by suppressing BMP signalling and thus, enhancing self-renewal and cancer stem cell-like traits of RCCs.
- Bo Jiang
- , Xiaozhi Zhao
- & Hongqian Guo
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Article
| Open AccessNetwork-based machine learning approach to predict immunotherapy response in cancer patients
Identifying biomarkers for response to immunotherapy in cancer remains challenging. Here, the authors develop an approach based on network biology and machine learning -NetBio- to identify molecular biomarkers of response to immunotherapy across different cancer types and cohorts.
- JungHo Kong
- , Doyeon Ha
- & Sanguk Kim
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Article
| Open AccessDynamic nucleosome landscape elicits a noncanonical GATA2 pioneer model
Here the authors provide a multi-omic study of the nucleosome landscape in LNCaP cells and observe nine functional nucleosome states each with characteristic nucleosome footprints. Upon androgen stimulation, they observed changes in these nucleosome states accompanied by changes in binding and function of pioneer factors, including GATA2.
- Tianbao Li
- , Qi Liu
- & Victor X. Jin
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Article
| Open AccessTargeting dual-specificity tyrosine phosphorylation-regulated kinase 2 with a highly selective inhibitor for the treatment of prostate cancer
The kinase DYRK2 is a known oncogene but its role in prostate cancer is unexplored. Here, the authors identify DYRK2 as a target for prostate cancer with a role in invasion and they discover a specific DYRK2 inhibitor that has good pharmacokinetics and efficacy in vivo.
- Kai Yuan
- , Zhaoxing Li
- & Peng Yang
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Article
| Open AccessTUBB4A interacts with MYH9 to protect the nucleus during cell migration and promotes prostate cancer via GSK3β/β-catenin signalling
The β-tubulin family protein TUBB4A is highly expressed in cancer but it’s molecular role is unclear. Here, the authors show that TUBB4A is required to protect the nucleus from genomic instability during migration and that it’s over expression promotes cancer progression.
- Song Gao
- , Shuaibin Wang
- & Lizhong Wang
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Article
| Open AccessMYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets
The role of MYC in transcriptional reprogramming in prostate cancer remains poorly characterized. Here, MYC overexpression antagonizes the canonical AR transcriptional program leading to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.
- Xintao Qiu
- , Nadia Boufaied
- & David P. Labbé
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Article
| Open AccessAlterations in homologous recombination repair genes in prostate cancer brain metastases
The diagnosis of prostate cancer brain metastasis (PCBM) has increased. Here, the authors investigate the landscape of somatic genetic alterations in brain metastases in a PCBM cohort of 51 patients with non-synchronous matched primary samples available for 20 patients.
- Antonio Rodriguez-Calero
- , John Gallon
- & Mark A. Rubin
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Article
| Open AccessASCL1 activates neuronal stem cell-like lineage programming through remodeling of the chromatin landscape in prostate cancer
Following androgen receptor pathway inhibition prostate cancers can differentiate towards the neuroendocrine lineage. Here, the authors identify epigenetic alterations regulated by ASCL1 and suggest targeting ASCL1 to reverse the neuroendocrine phenotype.
- Shaghayegh Nouruzi
- , Dwaipayan Ganguli
- & Amina Zoubeidi
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Article
| Open AccessTRMT6/61A-dependent base methylation of tRNA-derived fragments regulates gene-silencing activity and the unfolded protein response in bladder cancer
RNA modifications are important regulators of RNA biology. Here we report N1-methyladenosine (m1A) enrichment on 22-nucleotide tRNA fragments and its effect on gene-silencing. Higher level of m1A in bladder cancer is accompanied by gene dysregulation in unfolded protein response.
- Zhangli Su
- , Ida Monshaugen
- & Anindya Dutta
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Article
| Open AccessA proteogenomic analysis of clear cell renal cell carcinoma in a Chinese population
Clear cell renal cell carcinoma is an aggressive form of renal cancer, with differences in genomic mutations reported between Western and Eastern populations. In this study, the authors have compiled proteogenomic analysis of Chinese ccRCC to reveal genomic alterations and dysregulation of immune and metabolic responses.
- Yuanyuan Qu
- , Jinwen Feng
- & Chen Ding
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Article
| Open AccessDistinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors
How resistance to different classes of AKT inhibitors can emerge is unclear. Here, the authors show that resistance to allosteric inhibitors is mainly due to mutation of AKT1 while the ATP competitive resistance is driven by activation of PIM kinases in prostate cancer models.
- Kristin M. Zimmerman Savill
- , Brian B. Lee
- & Kui Lin
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Article
| Open AccessNeoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma
Immune checkpoint blockade therapy is successful in a high proportion of cancer patients, but others remain unresponsive. Authors here show that therapeutic success might be predictable in metastatic bladder cancer by longitudinal analysis of the early neoantigen-specific CD8 T cell response in peripheral blood.
- Jeppe Sejerø Holm
- , Samuel A. Funt
- & Sine Reker Hadrup
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Article
| Open AccessPredictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial
Identification of biomarkers to stratify patients who might benefit from treatment is needed to optimize targeted therapies. Here, based on an analysis of the RANGE trial (NCT02426125), the authors report potentially predictive biomarkers for survival benefit in patients with platinum-refractory advanced urothelial carcinoma treated with the anti-VEGFR2 monoclonal antibody ramucirumab.
- Michiel S. van der Heijden
- , Thomas Powles
- & Alexandra Drakaki
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Article
| Open AccessMTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers
The deficiency of MTAP, an enzyme of the adenine salvage pathway, occurs in some cancers. Here the authors perform a small cohort phase II clinical trial with metastatic MTAP-deficient urothelial cancer (UC) and show an increased overall response when comparing to MTAP-proficient UC patients.
- Omar Alhalabi
- , Jianfeng Chen
- & Jianjun Gao
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Article
| Open AccessSerum proteomics links suppression of tumor immunity to ancestry and lethal prostate cancer
Ancestry-related differences in immunobiology may explain the health disparities observed in prostate cancer patients, with men of African origin bearing the highest prostate cancer burden. By measuring immune-related proteins in serum samples, here the authors report that systemic cytokines linked to suppression of tumor immunity are upregulated in men of African ancestry and associated with reduced survival.
- Tsion Zewdu Minas
- , Julián Candia
- & Stefan Ambs
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Article
| Open AccessCell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors
Chemoimmunotherapy recently failed to improve objective response for patients with advanced muscle-invasive bladder cancer (MIBC). Here using two murine models of immune-excluded MIBC, the authors show that resistance to chemoimmunotherapy can be overcome by blocking the COX-2/prostaglandin E2 axis, reinvigorating anti-tumor immune responses.
- Fotis Nikolos
- , Kazukuni Hayashi
- & Keith Syson Chan
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Article
| Open AccessGermline mutation landscape of DNA damage repair genes in African Americans with prostate cancer highlights potentially targetable RAD genes
DNA damage repair genes have been linked with increased aggressiveness of prostate cancer, however, the extent of mutation of these genes has not been analyzed within a cohort of African American patients. Here, the authors identify increased mutation rates in specific DNA repair genes, compared with prostate cancer patients with European Ancestry.
- Indu Kohaar
- , Xijun Zhang
- & Gyorgy Petrovics
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Article
| Open AccessReceptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis
Distant metastasis is a major reason for mortality in patients with prostate cancer (PC). Here, the authors show that receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and its targeting impairs PC metastasis development.
- Yiwu Yan
- , Bo Zhou
- & Wei Yang
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Article
| Open AccessHyperpolarised 13C-MRI identifies the emergence of a glycolytic cell population within intermediate-risk human prostate cancer
Your paper will be accompanied by the following editor’s summary. Please let us know if there are any inaccuracies: ‘Hyperpolarised ¹³C-MRI is used to image cancer metabolism. Here the authors use this technique in prostate cancer and show that it can differentiate distinct disease states.
- Nikita Sushentsev
- , Mary A. McLean
- & Ferdia A. Gallagher
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Article
| Open AccessSingle-cell chromatin accessibility landscape in kidney identifies additional cell-of-origin in heterogenous papillary renal cell carcinoma
The heterogeneity of cell-of-origin for papillary renal cell carcinoma (pRCC) remains unknown. Here, with single-cell ATAC-seq from normal human kidney cells and ATACseq profiles from pRCC samples, the authors show that pRCC can originate from kidney collecting duct principal cells and this subtype is associated with advanced pRCC.
- Qi Wang
- , Yang Zhang
- & Jingping Yang
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Article
| Open AccessSingle-cell analysis of human primary prostate cancer reveals the heterogeneity of tumor-associated epithelial cell states
The changes that prostate cancer (PCa) induces in its microenvironment are not fully understood. Here the authors use single-cell RNA-seq and organoids to characterise how the microenvironment responds to PCa, and also identify tumour-associated epithelial cell states and club cells.
- Hanbing Song
- , Hannah N. W. Weinstein
- & Franklin W. Huang
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Article
| 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 AccessPilot study of Tremelimumab with and without cryoablation in patients with metastatic renal cell carcinoma
Anti-CTLA4 therapy has not been comprehensively explored for the treatment of metastatic renal cell carcinoma (mRCC). Here, in a pilot study of anti-CTLA4 therapy with or without cryoablation in mRCC, the authors report that the combination is feasible and enhances immune infiltration in patients with metastatic clear cell histology.
- Matthew T. Campbell
- , Surena F. Matin
- & Padmanee Sharma
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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 AccessPparg signaling controls bladder cancer subtype and immune exclusion
PPARg is differentially expressed in bladder cancer subtypes. Here, the authors show in mice that when an activated form of PPARg is expressed in basal bladder cells tumours do not form, however in the presence of injury the basal cells differentiate into luminal cells.
- Tiffany Tate
- , Tina Xiang
- & Cathy Lee Mendelsohn