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| Open AccessImmune features are associated with response to neoadjuvant chemo-immunotherapy for muscle-invasive bladder cancer
In the phase 2 study LCCC1520 (NCT02690558), clinical activity of pembrolizumab in combination with gemcitabine and cisplatin as neoadjuvant therapy in patients with muscle-invasive bladder cancer has been reported. Here the authors present molecular and immune cellular features associated with response to neoadjuvant chemo-immunotherapy.
- Wolfgang Beckabir
- , Mi Zhou
- & Benjamin G. Vincent
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Article
| Open AccessIntegrative multi-region molecular profiling of primary prostate cancer in men with synchronous lymph node metastasis
While it is known that localised prostate cancer is characterised by clonal heterogeneity, the clonal origin of synchronous lymph node (LN) metastases remains poorly understood. Here, the authors analyse the clonal origin of LN metastases in prostate cancer patients using multi-region sequencing.
- Udit Singhal
- , Srinivas Nallandhighal
- & Simpa S. Salami
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Article
| Open AccessHigh clonal diversity and spatial genetic admixture in early prostate cancer and surrounding normal tissue
It remains challenging to characterise somatic copy number alterations (SCNAs) in tumors and the surrounding tissues with spatial and single-cell resolution. Here, the authors develop the scCUTseq approach to characterise SCNAs from single cells in multi-region prostate cancer samples and identify pseudo-diploid cells and subclones.
- Ning Zhang
- , Luuk Harbers
- & Nicola Crosetto
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Article
| Open AccessThe gut microbiome-prostate cancer crosstalk is modulated by dietary polyunsaturated long-chain fatty acids
Here, using murine models of prostate cancer, the authors show that reduced fecal microbiota alpha-diversity correlates with increased prostate tumor burden, and that Omega-3 prebiotic supplementation reduces prostate cancer up-grading associated with a reduction of gut Ruminococcaceae and fecal butyrate levels.
- Gabriel Lachance
- , Karine Robitaille
- & Vincent Fradet
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Article
| Open AccessCD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancer
Tumor associated macrophages (TAM) are playing an active role in tumor immune evasion in multiple cancer type. Here authors show that CD276 expression by TAMs may underpin this immune-suppressive role via promoting efferocytosis and suppressing MHC class II expression, which result in decreased CD4+ and CD8 + T cell infiltration.
- Maosheng Cheng
- , Shuang Chen
- & Liang Peng
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Article
| Open AccessSpatial relationships in the urothelial and head and neck tumor microenvironment predict response to combination immune checkpoint inhibitors
Spatial positioning of cells within the tumour microenvironment may have a function in the success of immune checkpoint immunotherapy (ICI). Here the authors analyse spatial relationships from immunohistochemistry samples prior to ICI therapy and show that CD8 T cell or macrophage proximity to cancer cells is associated with better responses.
- Alberto Gil-Jimenez
- , Nick van Dijk
- & Lodewyk F. A. Wessels
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Article
| Open AccessThe evolution of metastatic upper tract urothelial carcinoma through genomic-transcriptomic and single-cell protein markers analysis
Detailed molecular studies are required to understand the differences between primary and metastatic upper tract urothelial carcinoma (UTUC). Here, the authors use genomics, transcriptomics and imaging mass cytometry to characterise the molecular profiles of primary and metastatic UTUC, and find that molecular subtypes remain highly conserved.
- Kentaro Ohara
- , André Figueiredo Rendeiro
- & Juan Miguel Mosquera
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Article
| Open AccessCRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression
The molecular basis of the metastatic disease in prostate cancer remains poorly characterised. Here, the authors investigate the interaction of tumor suppressor and epigenetic factor genes and highlight the role of Kmt2c deficiency in facilitating lung metastasis.
- Huiqiang Cai
- , Bin Zhang
- & Martin K. Thomsen
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Article
| Open AccessPrediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer
Metastatic castration-resistant prostate cancer is a highly aggressive disease, with a variable response to treatment. Here, the authors validate ctDNA fraction as a poor prognostic factor and develop a model to predict whether patients harbor sufficient ctDNA for informative blood-based genotyping.
- Nicolette M. Fonseca
- , Corinne Maurice-Dror
- & Alexander W. Wyatt
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Article
| Open AccessGene-expression-based T-Cell-to-Stroma Enrichment (TSE) score predicts response to immune checkpoint inhibitors in urothelial cancer
Immune checkpoint inhibitor treatment improves overall survival in metastatic urothelial cancer, but response of individual patients varies significantly. Authors here perform whole-genome DNA and bulk RNA sequencing on samples from metastatic tumours and based on these data, they set up a single metric, T cell-to-stroma enrichment (TSE) score, that reflects the relative abundance of T cells versus stromal cells and their products, accurately predicting therapeutic outcome.
- Maud Rijnders
- , J. Alberto Nakauma-González
- & Martijn P. Lolkema
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Article
| Open AccessThe IL6/JAK/STAT3 signaling axis is a therapeutic vulnerability in SMARCB1-deficient bladder cancer
SMARCB1 is frequently lost in solid cancer and reported to support tumourigenesis through STAT3 activation. Here, the authors show in several preclinical models that targeting IL6/JAK/STAT3 molecular pathway is a potential therapeutic approach for SMARCB1-deficient bladder cancer.
- Chandra Sekhar Amara
- , Karthik Reddy Kami Reddy
- & Nagireddy Putluri
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Article
| Open AccessAndrogen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation
The molecular mechanisms underlying Double-Null Prostate Cancer (DNPC) pathogenesis remain elusive. Here, the authors show that co-activation of HGF/MET and Wnt/β-catenin signaling in mouse prostates results in DNPC-like tumor lesions with elevated expression of XPO1 and ribosomal proteins.
- Won Kyung Kim
- , Alyssa J. Buckley
- & Zijie Sun
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Article
| Open AccessDurvalumab and guadecitabine in advanced clear cell renal cell carcinoma: results from the phase Ib/II study BTCRC-GU16-043
Preclinical studies have suggested the synergistic effect of epigenetic modulators and immunotherapy. Here the authors report the results of a phase Ib/II trial of durvalumab and guadecitabine in advanced clear cell renal cell carcinoma.
- Yousef Zakharia
- , Eric A. Singer
- & Ajjai Alva
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Article
| Open AccessMechanism-centric regulatory network identifies NME2 and MYC programs as markers of Enzalutamide resistance in CRPC
Heterogeneous response to Enzalutamide remains a critical issue in castration-resistant prostate cancer (CRPC). Here, the authors reconstruct a CRPC-specific mechanism-centric regulatory network to identify signatures of Enzalutamide response and predict patients at risk of Enzalutamide resistance.
- Sukanya Panja
- , Mihai Ioan Truica
- & Antonina Mitrofanova
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Article
| Open AccessDistinct mesenchymal cell states mediate prostate cancer progression
The components of the tumour microenvironment contribute to prostate cancer initiation and progression. Here the authors perform single-cell RNA sequencing and spatial transcriptomics analysis of prostate cancer stroma from mouse models at different stages of the disease and develop a gene signature to predict distant metastasis in patients.
- Hubert Pakula
- , Mohamed Omar
- & Massimo Loda
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Article
| Open AccessBipolar androgen therapy plus nivolumab for patients with metastatic castration-resistant prostate cancer: the COMBAT phase II trial
Bipolar androgen therapy (BAT) is a treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Here the authors report the results of a phase 2 trial of BAT plus nivolumab (anti-PD1) in patients with advanced mCRPC.
- Mark C. Markowski
- , Mary-Ellen Taplin
- & Emmanuel S. Antonarakis
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Article
| Open AccessGenetic and epigenetic features of bilateral Wilms tumor predisposition in patients from the Children’s Oncology Group AREN18B5-Q
The genetic and epigenetic predisposition of bilateral Wilms tumour remains to be investigated. Here, the authors perform multiomics analysis and identify the predominant genetic and epigenetic events associated with bilateral Wilms tumour predisposition.
- Andrew J. Murphy
- , Changde Cheng
- & Xiang Chen
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Article
| Open AccessGenomic and epigenomic integrative subtypes of renal cell carcinoma in a Japanese cohort
Renal cell carcinoma (RCC) subtypes are associated with different molecular alterations and clinical outcomes, but they need to be characterised in diverse cohorts. Here, the authors perform genomic, transcriptomic, and epigenomic profiling in a large cohort of Japanese RCC cases, and identify epi-subtypes associated with a particular immune environment.
- Akihiko Fukagawa
- , Natsuko Hama
- & Tatsuhiro Shibata
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Article
| Open AccessProstate cancer genetic risk and associated aggressive disease in men of African ancestry
Most genetic studies for prostate cancer have been performed outside the context of Sub-Saharan Africa. Here, the authors interrogate 247,780 exomic variants for 798 Black South African men and identify genes associated with aggressive disease.
- Pamela X. Y. Soh
- , Naledi Mmekwa
- & Vanessa M. Hayes
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Article
| Open AccessThe ELAVL3/MYCN positive feedback loop provides a therapeutic target for neuroendocrine prostate cancer
Neuroendocrine prostate cancer (NEPC) is an aggressive subtype with limited effective therapeutic options. Here, the authors identify the RNA-binding protein ELAVL3 as a driver of differentiation into NEPC via a positive feedback loop with MYCN and demonstrate the use of the repurposed drug pyrvinium pamoate to target this axis using preclinical models of NEPC.
- Yiyi Ji
- , Weiwei Zhang
- & Wei Xue
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Article
| Open AccessSETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer
SET domain–containing 2 (SETD2) is reported as an immunosuppressor in clear cell renal cell carcinoma (ccRCC). Here the authors show that SETD2 loss enhances de novo sphingomyelin biosynthesis during the transition from polycystic kidney disease to ccRCC.
- Hanyu Rao
- , Changwei Liu
- & Xianting Ding
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Article
| Open AccessSND1 binds to ERG and promotes tumor growth in genetic mouse models of prostate cancer
The ETS family transcription factor ERG is frequently overexpressed in prostate cancer and known to have a role in carcinogenesis, however, the underlying mechanism is less understood. Here, the authors report an interaction between ERG and SND1 as necessary for ERG-driven prostate cancer initiation using preclinical models.
- Sheng-You Liao
- , Dmytro Rudoy
- & Valeri Vasioukhin
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Article
| Open AccessReconstructing disease dynamics for mechanistic insights and clinical benefit
Understanding disease progression dynamics is critical for diagnostics and treatment, but capturing dynamics is difficult. Here, the authors present a method for modelling disease progression from high dimensional molecular data that enables patient stratification and high-risk disease state identification, showcased in bladder cancer.
- Amit Frishberg
- , Neta Milman
- & Shai S. Shen-Orr
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Article
| Open AccessPhagocytosis-initiated tumor hybrid cells acquire a c-Myc-mediated quasi-polarization state for immunoevasion and distant dissemination
The CD47/SIRPα axis is well known to mediate immune escape by promoting cancer resistance to phagocytosis. Here the authors show that low CD47-expressing prostate cancer cells still allow phagocytosis but the process is incomplete leading to the formation of macrophage:tumor hybrid cells with immune evasive and pro-metastatic properties.
- Chih-Wei Chou
- , Chia-Nung Hung
- & Tim Hui-Ming Huang
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Article
| Open AccessTargetable NOTCH1 rearrangements in reninoma
Reninomas are very rare kidney tumours of juxtaglomerular cells. Here, the authors analyse reninomas using whole-genome and transcriptome sequencing, and reveal the presence and functional effects of NOTCH1 rearrangements.
- Taryn D. Treger
- , John E. G. Lawrence
- & Tanzina Chowdhury
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Article
| Open AccessProteogenomics of different urothelial bladder cancer stages reveals distinct molecular features for papillary cancer and carcinoma in situ
Urothelial bladder cancer (UC) progression occurs as a multi-step process that leads to different kinds of lesions and subtypes. Here, the authors characterise benign and invasive lesions that occur during UC progression using proteogenomics in patient samples and show critical molecular pathways and prognostic associations.
- Zhenmei Yao
- , Ning Xu
- & Chen Ding
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Article
| Open AccessAhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer
An effective response to chemotherapy is often associated with the promotion of type-I interferons and anti-tumor immune responses. Here the authors show that tryptophan metabolites induced by chemo-drugs interfere with STING activation and IFN-I production in bladder cancer, reducing the efficacy of chemotherapy.
- Zikun Ma
- , Zhiyong Li
- & Xiaoyu Liang
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Article
| Open AccessLoss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance
Loss of PP2A activity is often associated with cancer but the underlying mechanism remains unclear. Here, the authors show that decreased methylation of PP2A catalytic C subunit caused by loss of LCMT-1 in prostate cancer abrogates the tumor suppressor activity of PP2A on AR/MED1-dependent gene expression, proposing decreased methyl-PP2A-C as a prognostic marker for prostate cancer progression.
- Reyaz ur Rasool
- , Caitlin M. O’Connor
- & Irfan A. Asangani
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Article
| Open AccessAndrogen receptor binding sites enabling genetic prediction of mortality due to prostate cancer in cancer-free subjects
The prediction of mortality due to prostate cancer remains challenging. Here, the authors perform trans-ancestry metaanalysis with a focus on binding sites of the androgen receptor and develop a polygenic risk score.
- Shuji Ito
- , Xiaoxi Liu
- & Chikashi Terao
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Article
| Open AccessA biallelic multiple nucleotide length polymorphism explains functional causality at 5p15.33 prostate cancer risk locus
Here, the authors functionally characterize a complex genetic variant relevant in prostate cancer that regulates IRX4 expression through epigenetic activation. This work highlights the significance of non-single nucleotide polymorphism causal variants in explaining disease risk.
- Sandor Spisak
- , Viktoria Tisza
- & Matthew L. Freedman
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Article
| Open AccessCopy number architectures define treatment-mediated selection of lethal prostate cancer clones
The heterogeneity of androgen receptor (AR) gene alterations across metastases in prostate cancer remains unresolved. Here, the authors characterise AR genomic complexity across spatially separated lethal metastases from 10 prostate cancer patients and investigate how AR alterations evolve.
- A. M. Mahedi Hasan
- , Paolo Cremaschi
- & Gerhardt Attard
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Article
| Open AccessGain-of-function mutant p53 together with ERG proto-oncogene drive prostate cancer by beta-catenin activation and pyrimidine synthesis
TP53 alteration and TMPRSS2-ERG fusion are often found together in prostate cancer. Here, the authors show that gain-of-function mutant p53 collaborates with ERG proto-oncogene to drive prostate cancer tumourigenesis by activating beta-catenin expression and afterwards pyrimidine synthesis.
- Donglin Ding
- , Alexandra M. Blee
- & Haojie Huang
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Article
| Open AccessCirculating trans fatty acids are associated with prostate cancer in Ghanaian and American men
Analyses of the association between fatty acids and prostate cancer have often neglected African patients. Here, the authors analyse 24 circulating fatty acids in Ghanaian, African American, and European American men, and explore the associations with socio-demographic factors, diet, FADS1/2 locus, and prostate cancer.
- Tsion Zewdu Minas
- , Brittany D. Lord
- & Stefan Ambs
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Article
| Open AccessProteogenomics of clear cell renal cell carcinoma response to tyrosine kinase inhibitor
Many clear cell renal cell carcinoma (ccRCC) patients do not respond or develop resistance to tyrosine kinase inhibitors, such as Sunitinib. Here, the authors perform a proteogenomics analysis of Chinese ccRCC patients treated with Sunitinib and develop a multi-omics classifier to distinguish responders from non-responders.
- Hailiang Zhang
- , Lin Bai
- & Chen Ding
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Article
| Open AccessHistone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer
The molecular mechanisms underlying androgen production in prostate cancer remain to be explored. Here, the authors reveal an epigenetic mark, K130Ac on H2A, following dual-phosphorylation on SREBP1 promoting de novo androgen synthesis to overcome the pharmacological inhibition of androgen synthesis.
- Thanh Nguyen
- , Dhivya Sridaran
- & Nupam P. Mahajan
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Article
| Open AccessSMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance
The molecular mechanisms involved in the development of SMARCB1-deficient renal medullary carcinomas (RMCs) remain to be characterised. Here, the authors integrated RMC omics data to show that ferroptosis resistance contributes to transformation of renal thick ascending limb cells into several RMC cell states.
- Bujamin H. Vokshi
- , Guillaume Davidson
- & Gabriel G. Malouf
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Article
| Open AccessHyperphosphorylated PTEN exerts oncogenic properties
PTEN has tumor suppressive functions. Here the authors report that PTEN C-tail hyperphosphorylation promotes neoplastic growth through oncogenic activation of WNT signalling.
- Janine H. van Ree
- , Karthik B. Jeganathan
- & Jan M. van Deursen
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Article
| Open AccessDNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC
DNA polymerase 1 (POLD1) has an important role in DNA damage repair and is frequently upregulated in cancer. Here, the authors report a non-canonical role of POLD1 wherein it stabilises MYC protein, creating a positive feedback loop with POLD1 expression and driving bladder cancer progression and metastasis.
- Yejinpeng Wang
- , Lingao Ju
- & Xinghuan Wang
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Article
| Open AccessExpression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer
The response to checkpoint immunotherapy within bladder cancer patients is highly variable. Here, the authors use RNA-seq, ATAC-seq and digital spatial profiling of pre- and post-treatment samples from the PURE01 trial to identify subtypes associated with treatment response.
- A. Gordon Robertson
- , Khyati Meghani
- & Joshua J. Meeks
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Article
| Open AccessBladder cancer organoids as a functional system to model different disease stages and therapy response
Bladder cancer heterogeneity can limit treatment efficacy in individual patients. Here, the authors use patient derived organoids to develop a drug screening pipeline and identify markers of treatment response.
- Martina Minoli
- , Thomas Cantore
- & Marianna Kruithof-de Julio
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Article
| Open AccessTargeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy
Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a highly enriched cell surface antigen expressed in prostate cancer. Here the authors describe the design of STEAP1 directed CART cells and show their antitumor activity in preclinical models of prostate cancer, also in combination with a collagen binding domain-IL-12 fusion cytokine.
- Vipul Bhatia
- , Nikhil V. Kamat
- & John K. Lee
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Article
| Open AccessPredicting response to enzalutamide and abiraterone in metastatic prostate cancer using whole-omics machine learning
Prostate cancer is known to have a variable response to androgen receptor signalling inhibitors. Here, the authors use machine learning to predict response to therapy from genomic, transcriptomic and clinical data.
- Anouk C. de Jong
- , Alexandra Danyi
- & Martijn P. Lolkema
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Article
| Open AccessMYC reshapes CTCF-mediated chromatin architecture in prostate cancer
The functional link between MYC and CTCF in prostate cancer remains to be investigated. Here, the authors highlight the role of MYC in rewiring chromatin architecture by interacting with CTCF protein.
- Zhao Wei
- , Song Wang
- & Haiyang Guo
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Article
| Open AccessEpigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma
Tumour heterogeneity in clear cell renal cell carcinoma (ccRCC) remains to be investigated. Here, the integration of spatial omics, transcriptional and chromatin accessibility profiling at the single-nucleus level and bulk proteogenomics data reveal markers and pathways important for ccRCC.
- Yige Wu
- , Nadezhda V. Terekhanova
- & Feng Chen
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Article
| Open AccessDissecting the immune suppressive human prostate tumor microenvironment via integrated single-cell and spatial transcriptomic analyses
The immune suppressive tumour microenvironment drives recurrence and metastatic disease in prostate cancer. Here authors provide a detailed analysis of the microenvironment via single cell RNA sequencing and high-resolution spatial transcriptomics to identify tumour-dependent changes compared to healthy tissue.
- Taghreed Hirz
- , Shenglin Mei
- & David B. Sykes
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Comment
| Open AccessEpigenetic mechanisms underlying subtype heterogeneity and tumor recurrence in prostate cancer
Prostate cancer is a highly heterogeneous disease. Progression on androgen deprivation therapy (ADT) to castration-resistant (CRPC), or neuroendocrine prostate cancer (NEPC), is associated with poor patient survival. This comment highlights recent evidence on the epigenetic mechanisms underlying the emergence of lineage plasticity and neuroendocrine differentiation in treatment-resistant prostate tumors.
- Goutam Chakraborty
- , Kasmira Gupta
- & Natasha Kyprianou
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Article
| Open AccessEpigenomic charting and functional annotation of risk loci in renal cell carcinoma
The epigenomic landscape of renal cell carcinoma (RCC) remains to be explored. Here, integrative epigenomic analysis of primary human RCC samples and RCC GWAS risk SNPs identifies transcription-factor specific subtypes and enrichment of risk variants in allelically-imbalanced peaks.
- Amin H. Nassar
- , Sarah Abou Alaiwi
- & Matthew L. Freedman
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Article
| Open AccessCRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer
Identifying prostate cancer patients who may respond well to PARP inhibitors is important for their success in the clinic. Here, using a genome-wide CRISPR-Cas9 knockout screen, the authors identify MMS22L as a biomarker for sensitivity to PARP inhibition in BRCA1/2-proficient prostate cancer.
- Takuya Tsujino
- , Tomoaki Takai
- & Li Jia
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Article
| Open AccessEstimating diagnostic uncertainty in artificial intelligence assisted pathology using conformal prediction
Artificial intelligence prediction accuracy can be reduced with new data. Here, the authors utilise conformal prediction to reduce incorrect predictions in histopathological analysis of prostate cancer biopsies.
- Henrik Olsson
- , Kimmo Kartasalo
- & Martin Eklund