ORCID Profile
0000-0001-5347-5083
Current Organisation
University of Oxford
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Publisher: Springer Science and Business Media LLC
Date: 08-01-2021
Publisher: Springer Science and Business Media LLC
Date: 19-02-2021
DOI: 10.1038/S41598-021-83215-Y
Abstract: Prostate cancer (PCa) is the most common non-cutaneous cancer in men and a notable cause of cancer mortality when it metastasises. The unfolded protein response (UPR) can be cytoprotective but when acutely activated can lead to cell death. In this study, we sought to enhance the acute activation of the UPR using radiation and ONC201, an UPR activator. Treating PCa cells with ONC201 quickly increased the expression of all the key regulators of the UPR and reduced the oxidative phosphorylation, with cell death occurring 72 h later. We exploited this time lag to sensitize prostate cancer cells to radiation through short-term treatment with ONC201. To understand how priming occurred, we performed RNA-Seq analysis and found that ONC201 suppressed the expression of cell cycle and DNA repair factors. In conclusion, we have shown that ONC201 can prime enhanced radiation response.
Publisher: Cold Spring Harbor Laboratory
Date: 21-06-2019
DOI: 10.1101/679092
Abstract: We aimed to determine the effect of s le size on performance of polygenic hazard score (PHS) models in predicting the age at onset of prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training (34,444 s les) and testing (6,417 s les) sets. Two PHS model-building strategies were investigated. Established-SNP model considered 65 SNPs that had been associated with prostate cancer in the literature. A stepwise SNP selection was used to develop Discovery-SNP models. The performance of each PHS model was calculated for random sizes of the training set (1 to 30 thousand). The performance of a representative Established-SNP model was estimated for random sizes of the testing set (0.5 to 6 thousand). Mean HR 98/50 (hazard ratio of top 2% to the average in the test set) of the Established-SNP model increased from 1.73[95%CI: 1.69-1.77] to 2.41[2.40-2.43] when the number of training s les was increased from 1 to 30 thousand. The corresponding HR 98/50 of the Discovery-SNP model increased from 1.05[0.93-1.18] to 2.19[2.16-2.23]. HR 98/50 of a representative Established-SNP model using testing set s le sizes of 0.6 and 6 thousand observations were 1.78[1.70-1.85] and 1.73[1.71-1.76], respectively. We estimate that a study population of 20 to 30 thousand men is required to develop Discovery-SNP PHS models for prostate cancer. The required s le size could be reduced to 10 thousand s les, if a set of SNPs associated with the disease has already been established. Polygenic hazard scores represent a recent advancement in polygenic prediction to model the age of onset of various diseases, such as Alzheimer’s disease or prostate cancer. These scores accumulate small effect sizes from several tens of genetic variants and can be used to establish an in idual’s risk of experiencing an event relative to a control population across time. The largest barrier to the development of polygenic hazard scores is the large number of study subjects needed to develop the underlying models. We sought to understand the effect of varying the total number of s les on the performance of a polygenic hazard score in the context of prostate cancer. We found that the performance of the score did not appreciably change beyond 20 to 30 thousand observations when developing the model from scratch. However, when the discovery of the genetic variants can be borrowed from those already identified in the literature to be associated with the disease, the required number of s les is reduced to 10 thousand with no appreciable detriment in performance. We hope that these results can guide the design of future studies of polygenic scores in other diseases and demonstrate the importance of genome-wide association studies.
Publisher: Cold Spring Harbor Laboratory
Date: 23-09-2022
DOI: 10.1101/2022.09.23.509205
Abstract: Understanding the impact of radiotherapy on the evolution of treatment resistant prostate cancer is critical for selecting effective treatment combinations. Whilst activation of Type 1 interferon signalling is a hallmark of how cells respond to viral infection, in cancer cells, multiple stresses are known to activate this same response. In this study we have evaluated for the first time the changes in the interferon response induced by culturing prostate cancer cells under sphere- forming conditions and following irradiation. We report a conserved upregulated transcript profile for both conditions that is strongly associated with therapeutic resistance and cell survival in vitro and in vivo. The profile includes and is regulated by the Type 1 interferon master regulator IRF7 which, when depleted, delays tumour re-growth following irradiation. We immuno-stained two independent prostate cohorts for IRF7 and found that increased expression, particularly in cases with low PTEN expression, correlated with poor prognosis. To more comprehensively characterise the impact of IRF7 and radiation on cells, RNA-Seq was performed on IRF7 knockdown cells at different radiation doses. We identified a number of biological processes that were IRF7-dependent, including the formation of stem-like cell populations and also therapeutic vulnerabilities. For ex le, irradiation sensitised surviving cells to either a combination of an IKKε/TBK1 and a MEK inhibitor or treatment with an inhibitor of IDO1, an IRF7- dependent gene. Translationally our work suggests that IRF7 expression can be used to stratify patients who may not benefit from receiving radiotherapy alone but rather may benefit from treatment combinations. In two cohorts treated with radical intent, strong IRF7 staining was associated with disease-specific death implicating this pathway as a convergence point for therapeutic resistance in prostate and potentially other cancer types.
Publisher: Oxford University Press (OUP)
Date: 11-12-2015
DOI: 10.1093/JNCI/DJV371
Publisher: American Association for Cancer Research (AACR)
Date: 09-2020
DOI: 10.1158/1055-9965.EPI-19-1527
Abstract: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening. United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3–T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups. The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age. PHS provides in idualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS. Personalized genetic risk assessments could inform prostate cancer screening decisions.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22429005.V1
Abstract: Supplementary figures 1-9 and legends.
Publisher: Oxford University Press (OUP)
Date: 03-07-2020
Abstract: Functional impairment of the tumour suppressor PTEN is common in primary prostate cancer and has been linked to relapse post-radiotherapy (post-RT). Pre-clinical modelling supports elevated CXC chemokine signalling as a critical mediator of PTEN-depleted disease progression and therapeutic resistance. We assessed the correlation of PTEN deficiency with CXC chemokine signalling and its association with clinical outcomes. Gene expression analysis characterized a PTENLOW/CXCR1HIGH/CXCR2HIGH cluster of tumours that associates with earlier time to biochemical recurrence [hazard ratio (HR) 5.87 and 2.65, respectively] and development of systemic metastasis (HR 3.51). In vitro, CXCL signalling was further lified following exposure of PTEN-deficient prostate cancer cell lines to ionizing radiation (IR). Inhibition of CXCR1/2 signalling in PTEN-depleted cell-based models increased IR sensitivity. In vivo, administration of a CXCR1/2-targeted pepducin (x1/2pal-i3), or CXCR2-specific antagonist (AZD5069), in combination with IR to PTEN-deficient xenografts attenuated tumour growth and progression compared to control or IR alone. Post-mortem analysis confirmed that x1/2pal-i3 administration attenuated IR-induced CXCL signalling and anti-apoptotic protein expression. Interventions targeting CXC chemokine signalling may provide an effective strategy to combine with RT in locally advanced prostate cancer patients with known presence of PTEN-deficient foci.
Publisher: Springer Science and Business Media LLC
Date: 08-06-2020
Publisher: Public Library of Science (PLoS)
Date: 22-12-2015
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.EURURO.2017.03.027
Abstract: Approximately 4-25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy. To identify a molecular subgroup of prostate cancers with metastatic potential at presentation resulting in a high risk of recurrence following radical prostatectomy. Unsupervised hierarchical clustering was performed using gene expression data from 70 primary resections, 31 metastatic lymph nodes, and 25 normal prostate s les. Independent assay validation was performed using 322 radical prostatectomy s les from four sites with a mean follow-up of 50.3 months. Molecular subgroups were identified using unsupervised hierarchical clustering. A partial least squares approach was used to generate a gene expression assay. Relationships with outcome (time to biochemical and metastatic recurrence) were analysed using multivariable Cox regression and log-rank analysis. A molecular subgroup of primary prostate cancer with biology similar to metastatic disease was identified. A 70-transcript signature (metastatic assay) was developed and independently validated in the radical prostatectomy s les. Metastatic assay positive patients had increased risk of biochemical recurrence (multivariable hazard ratio [HR] 1.62 [1.13-2.33] p=0.0092) and metastatic recurrence (multivariable HR=3.20 [1.76-5.80] p=0.0001). A combined model with Cancer of the Prostate Risk Assessment post surgical (CAPRA-S) identified patients at an increased risk of biochemical and metastatic recurrence superior to either model alone (HR=2.67 [1.90-3.75] p<0.0001 and HR=7.53 [4.13-13.73] p<0.0001, respectively). The retrospective nature of the study is acknowledged as a potential limitation. The metastatic assay may identify a molecular subgroup of primary prostate cancers with metastatic potential. The metastatic assay may improve the ability to detect patients at risk of metastatic recurrence following radical prostatectomy. The impact of adjuvant therapies should be assessed in this higher-risk population.
Publisher: Elsevier BV
Date: 2018
Publisher: Cold Spring Harbor Laboratory
Date: 31-07-2019
DOI: 10.1101/710400
Abstract: Prostate cancer (PCa) is the most common non-cutaneous cancer in men and a notable cause of cancer mortality when it metastasises. Localised disease is mostly treated with surgery or radiotherapy. As PCa develops and treatment resistance emerges, the unfolded protein response (UPR) arises as an important adaptive biology co- lifying with key cancer drivers [1]. The UPR can be cytoprotective but when acutely activated can lead to cell death. In this study we sought to enhance the acute activation of the UPR using radiation and ONC201, previously reported to be an UPR activator [2]. We found that treating PCa cells with ONC201 quickly increases the expression of components in all arms of the UPR – ATF4, ATF6 and IRE1-XBP1 – culminating in the subsequent cell death. During this time window between UPR activation and cell death we tested the priming effect of short-term administration of ONC201 on radiation responses. Pre-treatment with ONC201 for 24 hours prior to irradiation led to enhanced cytotoxicity compared to radiation alone assessed by cell viability and clonogenic assays. With priming, RNA-Seq analysis showed a sustained suppression of transcripts encoding cell cycle regulators as well as components of the DNA damage response pathways. Phenotypically this was reflected in enhanced cell cycle arrest and induction of necrosis and apoptosis. Furthermore, we demonstrated that short-term administration of inhibitors of cell cycle regulators (Dinaciclib and BI2536), could replicate this priming effect. Thus, we propose future studies to assess the impact of the short-term administration of drugs targeting the UPR and cell cycle regulation to enhance radiotherapy response.
Publisher: American Association for Cancer Research (AACR)
Date: 05-02-2021
DOI: 10.1158/0008-5472.CAN-20-2511
Abstract: This study identifies phospholipid elongation as a new metabolic target of androgen action that is critical for prostate tumor metastasis.
Publisher: BMJ
Date: 10-01-2018
DOI: 10.1136/BMJ.J5757
Abstract: To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of in idual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. Multiple institutions that were members of international PRACTICAL consortium. All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men the validation dataset comprised 6411 men. Prediction with hazard score of age of onset of aggressive cancer in validation set. In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10 Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.
Publisher: Springer Science and Business Media LLC
Date: 31-03-2017
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22429005
Abstract: Supplementary figures 1-9 and legends.
Publisher: Impact Journals, LLC
Date: 11-03-2017
Publisher: Springer Science and Business Media LLC
Date: 20-09-2018
Publisher: Springer Science and Business Media LLC
Date: 23-02-2021
DOI: 10.1038/S41467-021-21287-0
Abstract: Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS 1 ) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS 2 (PHS 1 , adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS 2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p 10 −180 ). Comparing the 80 th /20 th PHS 2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS 2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6513210.V1
Abstract: Abstract The androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation of novel AR targeting therapies, outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen-regulated cellular processes to more effectively target the AR dependence of prostate cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark of enhanced AR signaling in prostate cancer, yet the relationship between AR and the lipidome remains undefined. Using mass spectrometry–based lipidomics, this study reveals increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgen-regulated changes to lipid metabolism. Potent and direct AR-mediated induction of ELOVL fatty acid elongase 5 (ELOVL5), an enzyme that catalyzes fatty acid elongation, was demonstrated in prostate cancer cells, xenografts, and clinical tumors. Assessment of mRNA and protein in large-scale data sets revealed ELOVL5 as the predominant ELOVL expressed and upregulated in prostate cancer compared with nonmalignant prostate. ELOVL5 depletion markedly altered mitochondrial morphology and function, leading to excess generation of reactive oxygen species and resulting in suppression of prostate cancer cell proliferation, 3D growth, and i in vivo /i tumor growth and metastasis. Supplementation with the monounsaturated fatty acid cis-vaccenic acid, a direct product of ELOVL5 elongation, reversed the oxidative stress and associated cell proliferation and migration effects of ELOVL5 knockdown. Collectively, these results identify lipid elongation as a protumorigenic metabolic pathway in prostate cancer that is androgen-regulated, critical for metastasis, and targetable via ELOVL5. Significance: This study identifies phospholipid elongation as a new metabolic target of androgen action that is critical for prostate tumor metastasis. /
Publisher: American Association for Cancer Research (AACR)
Date: 18-03-2022
DOI: 10.1158/1541-7786.MCR-21-0780
Abstract: Targeting hypoxia-induced signaling may extend the therapeutic benefit of enzalutamide, providing an improved treatment strategy for patients with resistant disease.
Publisher: Informa UK Limited
Date: 02-01-2016
Publisher: Cold Spring Harbor Laboratory
Date: 05-08-2023
DOI: 10.1101/2023.07.28.23293330
Abstract: Proteins are essential for the development and progression of cancer and for the human body’s defense against tumor onset. The availability of a large panel of protein measurements and whole exome sequence data in the UK Biobank has enabled the simultaneous examination of plasma protein associations with risk across multiple cancer sites and their potential role in cancer etiology. We investigated the associations of plasma proteins with incidence of 19 cancers and 9 cancer subsites in up to 44,645 middle-aged adults in the UK Biobank, who had measurements of 1,463 plasma proteins generated using Olink Explore Proximity Extension Assay in baseline blood s les (2006-2010). Using multivariable-adjusted Cox regression, we estimated the risk of each protein with each cancer overall and by time-to-diagnosis after correction for multiple-testing. Identified protein-cancer associations were further assessed in an analysis of cancer risk using cis -pQTL and exome-wide protein genetic scores (exGS) in all UK Biobank participants (n=337,543). We identified 371 proteins associated with the risk of at least one incident cancer, represented by a total of 621 protein-cancer associations. These proteins were associated with cancers of the blood (201 proteins), liver (131), kidney (51), lung (28), esophagus (22), colorectum (15), stomach (8), breast (5), prostate (3), endometrium (3), ovary (2), bladder (1), head and neck (1), and brain (1). 100 of these 621 protein-cancer associations persisted for cases diagnosed more than seven years after blood draw. Of these 621 associations, there was further support from cis -pQTL analyses for the etiological role of TNFRSF14 in risk of non-Hodgkin lymphoma (NHL), and from whole exome protein score (exGS) analyses for 28 other protein-cancer associations, including SRP14 and risk of leukemia. Proteins with directionally concordant evidence from long time-to-diagnosis analyses and from both cis -pQTL and exGS analyses were SFTPA2 for lung cancer, TNFRSF1B and CD74 for NHL, and ADAM8 for leukemia. For the first time using an integrated multi-omics and cross-cancer approach, we have comprehensively assessed the plasma proteome in relation to cancer risk and identified multiple novel etiological candidates. Differences in the levels of many circulating proteins were detectable more than seven years before cancer diagnosis while some of these are likely to be markers of early cancer processes that may inform risk stratification, and/or risk factors, concordant evidence from genetic analyses suggests that some may have a role in cancer development.
Publisher: Oxford University Press (OUP)
Date: 30-04-2014
DOI: 10.1093/IJE/DYU090
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Ian Mills.