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| 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 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 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 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 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 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 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 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 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 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 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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| 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 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 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
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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 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 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 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 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 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 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 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