Imperial College London

ProfessorCharlotteBevan

Faculty of MedicineDepartment of Surgery & Cancer

Professor of Cancer Biology
 
 
 
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Contact

 

charlotte.bevan Website

 
 
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Assistant

 

Mrs Suzy Ford +44 (0)20 7594 2135

 
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Location

 

139ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

99 results found

Buxton AK, Abbasova S, Bevan CL, Leach DAet al., 2022, Liver Microenvironment Response to Prostate Cancer Metastasis and Hormonal Therapy., Cancers (Basel), Vol: 14, ISSN: 2072-6694

Prostate cancer-associated deaths arise from disease progression and metastasis. Metastasis to the liver is associated with the worst clinical outcomes for prostate cancer patients, and these metastatic tumors can be particularly resistant to the currently widely used chemotherapy and hormonal therapies, such as anti-androgens which block androgen synthesis or directly target the androgen receptor. The incidence of liver metastases is reportedly increasing, with a potential correlation with use of anti-androgen therapies. A key player in prostate cancer progression and therapeutic response is the microenvironment of the tumor(s). This is a dynamic and adaptive collection of cells and proteins, which impart signals and stimuli that can alter biological processes within prostate cancer cells. Investigation in the prostate primary site has demonstrated that cells of the microenvironment are also responsive to hormones and hormonal therapies. In this review, we collate information about what happens when cancer moves to the liver: the types of prostate cancer cells that metastasize there, the response of resident mesenchymal cells of the liver, and how the interactions between the cancer cells and the microenvironment may be altered by hormonal therapy.

Journal article

Broomfield J, Kalofonou M, Pataillot-Meakin T, Powell SM, Fernandes RC, Moser N, Bevan CL, Georgiou Pet al., 2022, Detection of YAP1 and AR-V7 mRNA for prostate cancer prognosis using an ISFET lab-on-chip platform, ACS Sensors, Vol: 7, Pages: 3389-3398, ISSN: 2379-3694

Prostate cancer (PCa) is the second most common cause of male cancer-related death worldwide. The gold standard of treatment for advanced PCa is androgen deprivation therapy (ADT). However, eventual failure of ADT is common and leads to lethal metastatic castration-resistant PCa. As such, the detection of relevant biomarkers in the blood for drug resistance in metastatic castration-resistant PCa patients could lead to personalized treatment options. mRNA detection is often limited by the low specificity of qPCR assays which are restricted to specialized laboratories. Here, we present a novel reverse-transcription loop-mediated isothermal amplification assay and have demonstrated its capability for sensitive detection of AR-V7 and YAP1 RNA (3 × 101 RNA copies per reaction). This work presents a foundation for the detection of circulating mRNA in PCa on a non-invasive lab-on-chip device for use at the point-of-care. This technique was implemented onto a lab-on-chip platform integrating an array of chemical sensors (ion-sensitive field-effect transistors) for real-time detection of RNA. Detection of RNA presence was achieved through the translation of chemical signals into electrical readouts. Validation of this technique was conducted with rapid detection (<15 min) of extracted RNA from prostate cancer cell lines 22Rv1s and DU145s.

Journal article

Leach DA, Fernandes RC, Bevan CL, 2022, Cellular specificity of androgen receptor, coregulators, and pioneer factors in prostate cancer, Endocrine Oncology, Vol: 2, Pages: R112-R131

<jats:p>Androgen signalling, through the transcription factor androgen receptor (AR), is vital to all stages of prostate development and most prostate cancer progression. AR signalling controls differentiation, morphogenesis, and function of the prostate. It also drives proliferation and survival in prostate cancer cells as the tumour progresses; given this importance, it is the main therapeutic target for disseminated disease. AR is also essential in the surrounding stroma, for the embryonic development of the prostate and controlling epithelial glandular development. Stromal AR is also important in cancer initiation, regulating paracrine factors that excite cancer cell proliferation, but lower stromal AR expression correlates with shorter time to progression/worse outcomes. The profile of AR target genes is different between benign and cancerous epithelial cells, between castrate-resistant prostate cancer cells and treatment-naïve cancer cells, between metastatic and primary cancer cells, and between epithelial cells and fibroblasts. This is also true of AR DNA-binding profiles. Potentially regulating the cellular specificity of AR binding and action are pioneer factors and coregulators, which control and influence the ability of AR to bind to chromatin and regulate gene expression. The expression of these factors differs between benign and cancerous cells, as well as throughout disease progression. The expression profile is also different between fibroblast and mesenchymal cell types. The functional importance of coregulators and pioneer factors in androgen signalling makes them attractive therapeutic targets, but given the contextual expression of these factors, it is essential to understand their roles in different cancerous and cell-lineage states.</jats:p>

Journal article

Broomfield J, Kalofonou M, Pataillot-Meakin T, Powell SM, Moser N, Bevan CL, Georgiou Pet al., 2022, Detection of YAP1 and AR-V7 mRNA for Prostate Cancer prognosis using an ISFET Lab-On-Chip platform, Publisher: Cold Spring Harbor Laboratory

<jats:title>Abstract</jats:title><jats:p>Prostate cancer (PCa) is the second most common cause of male cancer-related death worldwide. The gold standard of treatment for advanced PCa is androgen deprivation therapy (ADT). However, eventual failure of ADT is common and leads to lethal metastatic castration resistant PCa (mCRPC). As such, the detection of relevant biomarkers in the blood for drug resistance in mCRPC patients could lead to personalized treatment options. mRNA detection is often limited by the low specificity of qPCR assays which are restricted to specialised laboratories. Here, we present a novel reversetranscription loop-mediated isothermal amplification (RT-LAMP) assay and have demonstrated its capability for sensitive detection of AR-V7 and YAP1 RNA (3×10<jats:sup>1</jats:sup> RNA copies per reaction). This work presents a foundation for the detection of circulating mRNA in PCa on a non-invasive Lab-on-chip (LoC) device for use at point-of-care. This technique was implemented onto a Lab-on-Chip platform integrating an array of chemical sensors (ion-sensitive field-effect transistors - ISFETs) for real-time detection of RNA. Detection of RNA presence was achieved through the translation of chemical signals into electrical readouts. Validation of this technique was conducted with rapid detection (<jats:italic>&lt;</jats:italic>15 min) of extracted RNA from prostate cancer cell lines 22Rv1s and DU145s.</jats:p>

Working paper

Constantin TA, Greenland KK, Varela-Carver A, Bevan CLet al., 2022, Transcription associated cyclin-dependent kinases as therapeutic targets for prostate cancer, Oncogene, Vol: 41, Pages: 3303-3315, ISSN: 0950-9232

Transcriptional deregulation has emerged as a hallmark of several cancer types. In metastatic castration-resistant prostate cancer, a stage in which systemic androgen deprivation therapies fail to show clinical benefit, transcriptional addiction to the androgen receptor is maintained in most patients. This has led to increased efforts to find novel therapies that prevent oncogenic transactivation of the androgen receptor. In this context, a group of druggable protein kinases, known as transcription associated cyclin-dependent kinases (tCDKs), show great potential as therapeutic targets. Despite initial reservations about targeting tCDKs due to their ubiquitous and prerequisite nature, preclinical studies showed that selectively inhibiting such kinases could provide sufficient therapeutic window to exert antitumour effects in the absence of systemic toxicity. As a result, several highly specific inhibitors are currently being trialled in solid tumours, including prostate cancer. This article summarises the roles of tCDKs in regulating gene transcription and highlights rationales for their targeting in prostate cancer. It provides an overview of the most recent developments in this therapeutic area, including the most recent clinical advances, and discusses the utility of tCDK inhibitors in combination with established cancer agents.

Journal article

Fletcher C, Deng L, Orafidiya F, Yuan W, Lorentzen M, Cyran O, Varela Carver A, Constantin T, Dobbs F, Figueiredo I, Gurel B, Parkes E, Bogdan D, Pereira R, Zhao S, Neeb A, Issa F, Hester J, Kudo H, Liu Y, Philippou Y, Bristow R, Knudsen K, Bryant R, Feng F, Reed S, Mills I, de Bono J, Bevan Cet al., 2022, A non-coding RNA balancing act: miR-346-induced DNA damage is limited by the long non-coding RNA NORAD in prostate cancer, Molecular Cancer, Vol: 21, ISSN: 1476-4598

Background: miR‑346 was identified as an activator of Androgen Receptor (AR) signalling that associates with DNA damage response (DDR)‑linked transcripts in prostate cancer (PC). We sought to delineate the impact of miR‑346 on DNA damage, and its potential as a therapeutic agent.Methods: RNA‑IP, RNA‑seq, RNA‑ISH, DNA fibre assays, in vivo xenograft studies and bioinformatics approaches were used alongside a novel method for amplification‑free, single nucleotide‑resolution genome‑wide mapping of DNA breaks (INDUCE‑seq).Results: miR‑346 induces rapid and extensive DNA damage in PC cells ‑ the first report of microRNA‑induced DNA damage. Mechanistically, this is achieved through transcriptional hyperactivation, R‑loop formation and replication stress, leading to checkpoint activation and cell cycle arrest. miR‑346 also interacts with genome‑protective lncRNA NORAD to disrupt its interaction with PUM2, leading to PUM2 stabilisation and its increased turnover of DNA damage response (DDR) transcripts. Confirming clinical relevance, NORAD expression and activity strongly correlate with poorPC clinical outcomes and increased DDR in biopsy RNA‑seq studies. In contrast, miR‑346 is associated with improved PC survival.INDUCE‑seq reveals that miR‑346‑induced DSBs occur preferentially at binding sites of the most highly‑transcriptionally active transcription factors in PC cells, including c‑Myc, FOXA1, HOXB13, NKX3.1, and importantly, AR, resulting in target transcript downregulation. Further, RNA‑seq reveals widespread miR‑346 and shNORAD dysregulation of DNAdamage, replication and cell cycle processes.NORAD drives target‑directed miR decay (TDMD) of miR‑346 as a novel genome protection mechanism: NORAD silencing increases mature miR‑346 levels by several thousand‑fold, and WT but not TDMD‑mutant NORAD rescues miR‑346‑induced DNA damage. Importantly, miR‑346 sensitises PC cells to DNA‑damaging drugs including PARP inhibitor and chemotherapy, and induces tumour regression as a m

Journal article

Bevan C, Pataillot-Meakin T, Ladame S, 2022, Technologies for size-based analysis of circulating cell free DNA: limitations and clinical implementation, Critical Reviews™ in Oncogenesis, ISSN: 0893-9675

Prostate cancer is the second most common malignancy in men worldwide, and incidence is likely to rise in the next decade. Screening options are limited as this has been shown to result in over-treatment of clinically insignificant disease. New biomarkers and technologies to detect them are therefore needed in order to better diagnose and stratify patients in primary care. Circulating cell-free DNA (ccfDNA) has gained interest as a potential minimally invasive biomarker, detectable in many bodily fluids (such as blood, urine, and cerebral spinal fluid) and reflecting the mutational landscape in tumours. More recently, the size distribution of ccfDNA fragments has also gained interest as a specific biomarker, where differences in size distribution have been observed between healthy volunteers and cancer patients, resulting in the new field of fragmentomics. Analysis of ccfDNA sizes provides avenues for alternative analytical technologies but commercial options are currently limited. Most focus on mutation detection and are subject to several biases that may affect size distribution. Here we discuss the available technologies and identify major issues and considerations that may affect their implementation as a clinically useful test based on ccfDNA size profiling.

Journal article

Orafidiya F, Deng L, Bevan C, Fletcher Cet al., 2022, Crosstalk between long non coding RNAs, microRNAs and DNA damage repair in prostate cancer: new therapeutic opportunities?, Cancers, Vol: 14, ISSN: 2072-6694

It is increasingly appreciated that transcripts derived from non-coding parts of the human genome, such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), are key regulators of biological processes both in normal physiology and disease. Their dysregulation during tumourigenesis has attracted significant interest in their exploitation as novel cancer therapeutics. Prostate cancer (PCa), as one of the most diagnosed malignancies and a leading cause of cancer-related death in men, continues to pose a major public health problem. In particular, survival of men with metastatic disease is very poor. Defects in DNA damage response (DDR) pathways culminate in genomic instability in PCa, which is associated with aggressive disease and poor patient outcome. Treatment options for metastatic PCa remain limited. Thus, researchers are increasingly targeting ncRNAs and DDR pathways to develop new biomarkers and therapeutics for PCa. Increasing evidence points to a widespread and biologically-relevant regulatory network of interactions between lncRNAs and miRNAs, with implications for major biological and pathological processes. This review summarises the current state of knowledge surrounding the roles of the lncRNA:miRNA interactions in PCa DDR, and their emerging potential as predictive and diagnostic biomarkers. We also discuss their therapeutic promise for the clinical management of PCa.

Journal article

Rana S, Valbuena GN, Curry E, Bevan CL, Keun HCet al., 2022, MicroRNAs as biomarkers for prostate cancer prognosis: a systematic review and a systematic reanalysis of public data, British Journal of Cancer, Vol: 126, Pages: 502-513, ISSN: 0007-0920

BackgroundReliable prognostic biomarkers to distinguish indolent from aggressive prostate cancer (PCa) are lacking. Many studies investigated microRNAs (miRs) as PCa prognostic biomarkers, often reporting inconsistent findings. We present a systematic review of these; also systematic reanalysis of public miR-profile datasets to identify tissue-derived miRs prognostic of biochemical recurrence (BCR) in patients undergoing radical prostatectomy.MethodsIndependent PubMed searches were performed for relevant articles from January 2007 to December 2019. For the review, 128 studies were included. Pooled-hazard-ratios (HRs) for miRs in multiple studies were calculated using a random-effects model (REM). For the reanalysis, five studies were included and Cox proportional-hazard models, testing miR association with BCR, performed for miRs profiled in all.ResultsSystematic review identified 120 miRs as prognostic. Five (let-7b-5p, miR-145-5p, miR152-3p, miR-195-5p, miR-224-5p) were consistently associated with progression in multiple cohorts/studies. In the reanalysis, ten (let-7a-5p, miR-148a-3p, miR-203a-3p, miR-26b-5p, miR30a-3p, miR-30c-5p, miR-30e-3p, miR-374a-5p, miR-425-3p, miR-582-5p) were significantly prognostic of BCR. Of these, miR-148a-3p (HR = 0.80/95% CI = 0.68-0.94) and miR-582-5p (HR = 0.73/95% CI = 0.61-0.87) were also reported in prior publication(s) in the review.ConclusionsFifteen miRs were consistently associated with disease progression in multiple publications or datasets. Further research into their biological roles is warranted to support investigations into their performance as prognostic PCa biomarkers.

Journal article

Blanquart E, Mandonnet A, Mars M, Cenac C, Anesi N, Mercier P, Audouard C, Roga S, de Almeida GS, Bevan CL, Girard J-P, Pelletier L, Laffont S, Guery J-Cet al., 2022, Targeting androgen signaling in ILC2s protects from IL-33-driven lung inflammation, independently of KLRG1, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 149, Pages: 237-+, ISSN: 0091-6749

Journal article

Fernandes RC, Leach DA, Bevan CL, 2022, Epigenetic Coregulation of Androgen Receptor Signaling., Adv Exp Med Biol, Vol: 1390, Pages: 277-293, ISSN: 0065-2598

The androgen receptor (AR) is a ligand-activated transcription factor belonging to the nuclear receptor (NR) superfamily. As with other members of the NR family, transcriptional activity of the AR is regulated by interactions with coregulatory proteins, which either enhance (coactivators) or repress (corepressors) its transcriptional activity. AR associated coregulators are functionally diverse, but a large fraction are epigenetic histone and chromatin modifiers. Epigenetic coregulators are recruited to gene regulatory regions as part of multi-protein complexes, often acting in a dynamic and inter-dependent manner to remodel chromatin, thereby allowing or inhibiting the access of AR-associated transcriptional machinery to target genes; functional consequences being regulation of transcriptional output. Epigenetic modifiers, including those that function as AR coregulators, are frequently mutated or aberrantly expressed in prostate cancer and are implicated in disease progression. Some of these modifiers are being investigated as therapeutic targets in several cancer types and could potentially be used to modulate aberrant AR activity in prostate cancer. In this chapter we will summarise the functional role of epigenetic coregulators in AR signalling, their dysregulation during prostate cancer progression and the current status of drugs targeting these enzymes.

Journal article

Leach DA, Brooke GN, Bevan CL, 2021, Roles of steroid receptors in the lung and COVID-19, Essays in Biochemistry, Vol: 65, Pages: 1025-1038, ISSN: 0071-1365

COVID-19 symptoms and mortality are largely due to its devastating effects in the lungs. The disease is caused by the SARS (Severe Acute Respiratory Syndrome)-CoV-2 coronavirus, which requires host cell proteins such as ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane serine protease 2) for infection of lung epithelia. The expression and function of the steroid hormone receptor family is important in many aspects that impact on COVID-19 effects in the lung – notably lung development and function, the immune system, and expression of TMPRSS2 and ACE2. This review provides a brief summary of current knowledge on the roles of the steroid hormone receptors [androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR), mineralocorticoid receptor (MR) and oestrogen receptor (ER)] in the lung, their effects on host cell proteins that facilitate SARS-CoV-2 uptake, and provides a snapshot of current clinical trials investigating the use of steroid receptor (SR) ligands to treat COVID-19.

Journal article

Bevan CL, 2021, Breaking down walls in prostate cancer with the MURAL collection of patient-derived xenografts, Nature Communications, Vol: 12, Pages: 1-3, ISSN: 2041-1723

Journal article

Leach DA, Mohr A, Giotis ES, Cil E, Isac AM, Yates LL, Barclay WS, Zwacka RM, Bevan C, Brooke GNet al., 2021, The antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells, Nature Communications, Vol: 12, Pages: 1-12, ISSN: 2041-1723

SARS-CoV-2 attacks various organs, most destructively the lung, and cellular entry requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; androgen receptor activation increases TMPRSS2 levels in various tissues, most notably prostate. We show here that treatment with the antiandrogen enzalutamide – a well-tolerated drug widely used in advanced prostate cancer – reduces TMPRSS2 levels in human lung cells and in mouse lung. Importantly, antiandrogens significantly reduced SARS-CoV-2 entry and infection in lung cells. In support of this experimental data, analysis of existing datasets shows striking co-expression of AR and TMPRSS2, including in specific lung cell types targeted by SARS-CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19.

Journal article

Fletcher C, Deng L, Orafidiya F, Yuan W, Figueiredo I, Gurel B, Leach D, Issa F, Neeb A, Bogdan D, Dobbs F, Philippou Y, Murphy EA, Zhao SG, Hester J, Bryant RJ, Reed SH, Knudsen KE, Mills IG, de Bono J, Bevan CLet al., 2021, Long non-coding RNA NORAD interaction with miR-346 impacts DNA damage response and anti-tumor immunity in prostate cancer., Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

Lovell S, Zhang L, Kryza T, Neodo A, Bock N, De Vita E, Williams E, Engelsberger E, Xu C, Bakker A, Maneiro M, Tanaka R, Bevan C, Clements J, Tate Eet al., 2021, A suite of activity-based probes to dissect the KLK activome in drug-resistant prostate cancer, Journal of the American Chemical Society, Vol: 143, Pages: 8911-8924, ISSN: 0002-7863

Kallikrein-related peptidases (KLKs) are a family of secreted serine proteases, which form a network (the KLK activome) with an important role in proteolysis and signaling. In prostate cancer (PCa), increased KLK activity promotes tumor growth and metastasis through multiple biochemical pathways, and specific quantification and tracking of changes in the KLK activome could contribute to validation of KLKs as potential drug targets. Herein we report a technology platform based on novel activity-based probes (ABPs) and inhibitors enabling simultaneous orthogonal analysis of KLK2, KLK3, and KLK14 activity in hormone-responsive PCa cell lines and tumor homogenates. Importantly, we identifed a significant decoupling of KLK activity and abundance and suggest that KLK proteolysis should be considered as an additional parameter, along with the PSA blood test, for accurate PCa diagnosis and monitoring. Using selective inhibitors and multiplexed fluorescent activity-based protein profiling (ABPP), we dissect the KLK activome in PCa cells and show that increased KLK14 activity leads to a migratory phenotype. Furthermore, using biotinylated ABPs, we show that active KLK molecules are secreted into the bone microenvironment by PCa cells following stimulation by osteoblasts suggesting KLK-mediated signaling mechanisms could contribute to PCa metastasis to bone. Together our findings show that ABPP is a powerful approach to dissect dysregulation of the KLK activome as a promising and previously underappreciated therapeutic target in advanced PCa.

Journal article

Cai S, Pataillot-Meakin T, Shibakawa A, Ren R, Bevan C, Ladame S, Ivanov A, Edel Jet al., 2021, Single-molecule amplification-free multiplexed detection of circulating microRNA cancer biomarkers from serum, Nature Communications, Vol: 12, ISSN: 2041-1723

MicroRNAs (miRNAs) play essential roles in post-transcriptional gene expression and are also found freely circulating in bodily fluids such as blood. Dysregulated miRNA signatures have been associated with many diseases including cancer, and miRNA profiling from liquid biopsies offers a promising strategy for cancer diagnosis, prognosis and monitoring. Here, we develop size-encoded molecular probes that can be used for simultaneous electro-optical nanopore sensing of miRNAs, allowing for ultrasensitive, sequence-specific and multiplexed detection directly in unprocessed human serum, in sample volumes as small as 0.1 μl. We show that this approach allows for femtomolar sensitivity and single-base mismatch selectivity. We demonstrate the ability to simultaneously monitor miRNAs (miR-141-3p and miR-375-3p) from prostate cancer patients with active disease and in remission. This technology can pave the way for next generation of minimally invasive diagnostic and companion diagnostic tests for cancer.

Journal article

Oduwole OO, Poliandri A, Okolo A, Rawson P, Doroszko M, Chrusciel M, Rahman NA, Serrano de Almeida G, Bevan CL, Koechling W, Huhtaniemi ITet al., 2021, Follicle-stimulating hormone promotes growth of human prostate cancer cell line-derived tumor xenografts, FASEB JOURNAL, Vol: 35, ISSN: 0892-6638

Journal article

Estebanez-Perpina E, Bevan CL, McEwan IJ, 2021, Eighty years of targeting androgen receptor activity in prostate cancer: the fight goes on, Cancers, Vol: 13, Pages: 1-19, ISSN: 2072-6694

Prostate cancer (PCa) is the most common cancer in men in the West, other than skin cancer, accounting for over a quarter of cancer diagnoses in US men. In a seminal paper from 1941, Huggins and Hodges demonstrated that prostate tumours and metastatic disease were sensitive to the presence or absence of androgenic hormones. The first hormonal therapy for PCa was thus castration. In the subsequent eighty years, targeting the androgen signalling axis, where possible using drugs rather than surgery, has been a mainstay in the treatment of advanced and metastatic disease. Androgens signal via the androgen receptor, a ligand-activated transcription factor, which is the direct target of many such drugs. In this review we discuss the role of the androgen receptor in PCa and how the combination of structural information and functional screenings is continuing to be used for the discovery of new drug to switch off the receptor or modify its function in cancer cells.

Journal article

Siddappa M, Wani SA, Long MD, Leach DA, Mathe EA, Bevan CL, Campbell MJet al., 2020, Identification of transcription factor co-regulators that drive prostate cancer progression, Scientific Reports, Vol: 10, Pages: 1-16, ISSN: 2045-2322

In prostate cancer (PCa), and many other hormone-dependent cancers, there is clear evidence for distorted transcriptional control as disease driver mechanisms. Defining which transcription factor (TF) and coregulators are altered and combine to become oncogenic drivers remains a challenge, in part because of the multitude of TFs and coregulators and the diverse genomic space on which they function. The current study was undertaken to identify which TFs and coregulators are commonly altered in PCa. We generated unique lists of TFs (n = 2662), coactivators (COA; n = 766); corepressors (COR; n = 599); mixed function coregulators (MIXED; n = 511), and to address the challenge of defining how these genes are altered we tested how expression, copy number alterations and mutation status varied across seven prostate cancer (PCa) cohorts (three of localized and four advanced disease). Testing of significant changes was undertaken by bootstrapping approaches and the most significant changes were identified. For one commonly and significantly altered gene were stably knocked-down expression and undertook cell biology experiments and RNA-Seq to identify differentially altered gene networks and their association with PCa progression risks. COAS, CORS, MIXED and TFs all displayed significant down-regulated expression (q.value < 0.1) and correlated with protein expression (r 0.4–0.55). In localized PCa, stringent expression filtering identified commonly altered TFs and coregulator genes, including well-established (e.g. ERG) and underexplored (e.g. PPARGC1A, encodes PGC1α). Reduced PPARGC1A expression significantly associated with worse disease-free survival in two cohorts of localized PCa. Stable PGC1α knockdown in LNCaP cells increased growth rates and invasiveness and RNA-Seq revealed a profound basal impact on gene expression (~ 2300 genes; FDR < 0.05, logFC&thins

Journal article

Jarvis S, Gethings LA, Samanta L, Pedroni SMA, Withers DJ, Gray N, Plumb RS, Winston RML, Williamson C, Bevan CLet al., 2020, High fat diet causes distinct aberrations in the testicular proteome, International Journal of Obesity, Vol: 44, Pages: 1958-1969, ISSN: 0307-0565

Diet has important effects on normal physiology and the potential deleterious effects of high fat diets and obesity on male reproductive health are being increasingly described. We conducted a histological review of the effects of chronic high fat (HF) diet (using a mouse model fed a 45% fat diet for 21 weeks) with a discovery proteomic study to assess for changes in the abundance of proteins in the testis. Mice on a HF diet became obese and developed glucose intolerance. Using mass spectrometry, we identify 102 proteins affected in the testis of obese mice. These included structural proteins important for the blood testis barrier (filamin A, FLNA), proteins involved in oxidative stress responses (spermatogenesis associated 20, SPATA-20) and lipid homoeostasis (sterol regulatory element-binding protein 2, SREBP2 and apolipoprotein A1, APOA1). In addition, an important regulator protein paraspeckle component 1, PSPC-1, which interacts with the androgen receptor was significantly downregulated. Proteomic data was validated using both Western blotting and immunostaining which confirmed and localised protein expression in both mouse and human testis using biopsy specimens. This study focused mainly on the abnormalities that occurred at the protein level and as a result, we have identified several candidate proteins and conducted pathway analysis around the effects of HF diet on the testis providing novel insights not previously described. Some of the identified targets could be targeted therapeutically and future work is directed in this area.

Journal article

Eringyte I, Zamarbide Losada JN, Powell SM, Bevan CL, Fletcher CEet al., 2020, Coordinated AR and microRNA regulation in prostate cancer, Asian Journal of Urology, Vol: 7, Pages: 233-250, ISSN: 2214-3882

The androgen receptor (AR) remains a key driver of prostate cancer (PCa) progression, even in the advanced castrate-resistant stage, where testicular androgens are absent. It is therefore of critical importance to understand the molecular mechanisms governing its activity and regulation during prostate tumourigenesis. MicroRNAs (miRs) are small ∼22 nt non-coding RNAs that regulate target gene, often through association with 3' untranslated regions (3'UTRs) of transcripts. They display dysregulation during cancer progression, can function as oncogenes or tumour suppressors, and are increasingly recognised as targets or regulators of hormonal action. Thus, understanding factors which modulate miRs synthesis is essential. There is increasing evidence for complex and dynamic bi-directional cross-talk between the multi-step miR biogenesis cascade and the AR signalling axis in PCa. This review summarises the wealth of mechanisms by which miRs are regulated by AR, and conversely, how miRs impact AR's transcriptional activity, including that of AR splice variants. In addition, we assess the implications of the convergence of these pathways on the clinical employment of miRs as PCa biomarkers and therapeutic targets.

Journal article

Connor MJ, Shah TT, Horan G, Bevan CL, Winkler M, Ahmed HUet al., 2020, Cytoreductive treatment strategies for de novo metastatic prostate cancer, NATURE REVIEWS CLINICAL ONCOLOGY, Vol: 17, Pages: 168-182, ISSN: 1759-4774

Journal article

Kalofonou F, Sita-Lumsden A, Leach D, Fletcher C, Waxman J, Bevan CLet al., 2020, MiR-27a-3p: An AR-modulatory microRNA with a distinct role in prostate cancer progression and therapy, Genitourinary Cancers Symposium of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X

Conference paper

Jarvis S, Williamson C, Bevan C, 2019, Liver X receptors and male (in)fertility, International Journal of Molecular Sciences, Vol: 20, ISSN: 1422-0067

Liver X receptors (LXRs) are ligand-dependent transcription factors acting as ‘cholesterol sensors’ to regulate lipid homeostasis in cells. The two isoforms, LXRα (NR1H3) and LXRβ (NR1H2), are differentially expressed, with the former expressed predominantly in metabolically active tissues and the latter more ubiquitously. Both are activated by oxidised cholesterol metabolites, endogenously produced oxysterols. LXRs have important roles in lipid metabolism and inflammation, plus a number of newly emerging roles. They are implicated in regulating lipid balance in normal male reproductive function and may provide a link between male infertility and lipid disorders and/or obesity. Studies from Lxr knockout mouse models provide compelling evidence to support this. More recently published data suggest distinct and overlapping roles of the LXR isoforms in the testis and recent evidence of a role for LXRs in human male fertility. This review summarises the current literature and explores the likely link between LXR, lipid metabolism and male fertility as part of a special issue on Liver X receptors in International Journal of Molecular Sciences.

Journal article

Hindley JW, Zheleva DG, Elani Y, Charalambous K, Barter LMC, Booth PJ, Bevan CL, Law RV, Ces Oet al., 2019, Building a synthetic mechanosensitive signaling pathway in compartmentalized artificial cells, Proceedings of the National Academy of Sciences, Vol: 116, Pages: 16711-16716, ISSN: 0027-8424

To date reconstitution of one of the fundamental methods of cell communication, the signaling pathway, has been unaddressed in the bottom-up construction of artificial cells (ACs). Such developments are needed to increase the functionality and biomimicry of ACs, accelerating their translation and application in biotechnology. Here we report the construction of a de novo synthetic signaling pathway in microscale nested vesicles. Vesicle cell models respond to external calcium signals through activation of an intracellular interaction between phospholipase A2 and a mechanosensitive channel present in the internal membranes, triggering content mixing between compartments and controlling cell fluorescence. Emulsion-based approaches to AC construction are therefore shown to be ideal for the quick design and testing of new signaling networks and can readily include synthetic molecules difficult to introduce to biological cells. This work represents a foundation for the engineering of multi-compartment-spanning designer pathways that can be utilised to control downstream events inside an artificial cell, leading to the assembly of micromachines capable of sensing and responding to changes in their local environment.

Journal article

Fletcher C, Sulpice E, Combe S, Shibakawa A, Leach D, Hamilton MP, Chrysostomou SL, Sharp A, Welti J, Yuan W, Dart D, Knight E, Ning J, Francis JC, Kounatidou EE, Gaughan L, Swain A, Lupold SE, De Bono JS, McGuire SE, Gidrol X, Bevan Cet al., 2019, Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer, Oncogene, Vol: 38, Pages: 5700-5724, ISSN: 0950-9232

Androgen receptor (AR) signalling is a key prostate cancer (PC) driver, even inadvanced ‘castrate-resistant’ disease (CRPC). To systematically identify microRNAs (miRs) modulating AR activity in lethal disease, hormone-responsive and -resistant PC cells expressing a luciferase-based AR reporter were transfected with a miR inhibitor library; 78 inhibitors significantly altered AR activity. Upon validation, miR-346, miR-361-3p and miR-197 inhibitors dramatically reduced AR transcriptional activity, mRNA and protein levels, increased apoptosis, reduced proliferation, repressed EMT, inhibited PC migration and invasion, demonstrating additive effects with AR inhibition. Corresponding miRs increased AR activity through a novel and anti-dogmatic mechanism of direct association with AR 6.9kb 3’UTR and transcript stabilisation. In addition, miR-346 and miR-361-3p modulation altered levels of constitutively-active AR variants, and inhibited variant-driven PC cell proliferation, so may contribute to persistent AR signalling in CRPC in the absence of circulating androgens. Pathway analysis of AGO-PAR-CLIP-identified miR targets revealed roles in DNA replication and repair, cell cycle, signal transduction and immune function. Silencing these targets, including tumour suppressors ARHGDIA and TAGLN2, phenocopied miR effects, demonstrating physiological relevance. MiR-346 additionally upregulated the oncogene, YWHAZ, which correlated with grade, biochemical relapse and metastasis in patients. These AR-modulatory miRs and targets correlated with AR activity in patient biopsies, and were elevated in response to long-term enzalutamide treatment of patient-derived CRPC xenografts. In summary, we identified miRs that modulate AR activity in PC and CRPC, via novel mechanisms, and may represent novel PC the

Journal article

Kalofonou F, Leach D, Hamilton M, Mcguire SE, Fletcher C, Waxman J, Bevan CLet al., 2019, MiR-1271-5p: An AR-modulatory microRNA with a distinct role in prostate cancer progression, through SND1 and MORF4L1 interaction., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X

Conference paper

Wang C, Datoo T, Zhao H, Wu L, Date A, Jiang C, Sanders RD, Wang G, Bevan C, Ma Det al., 2018, Midazolam and Dexmedetomidine Affect Neuroglioma and Lung Carcinoma Cell Biology In Vitro and In Vivo, ANESTHESIOLOGY, Vol: 129, Pages: 1000-1014, ISSN: 0003-3022

Journal article

Dart DA, Kandil S, Tommasini-Ghelfi S, Serrano de Almeida G, Bevan CL, Jiang W, Westwell ADet al., 2018, Novel trifluoromethylated enobosarm analogues with potent anti-androgenic activity in vitro and tissue selectivity in vivo, Molecular Cancer Therapeutics, Vol: 17, Pages: 1846-1858, ISSN: 1535-7163

Prostate cancer often develops anti-androgen resistance, possibly via androgen receptor (AR) mutations which change antagonists to agonists. Novel therapies with increased anticancer activity, whilst overcoming current drug resistance are urgently needed. Enobosarm has anabolic effects on muscle and bone whilst having no effect on the prostate. Here we describe the activity of novel chemically modified enobosarm analogues. The rational addition of bis-trifluoromethyl groups into ring B of enobosarm, profoundly modified their activity, pharmacokinetic and tissue distribution profiles. These chemical structural modifications resulted in an improved AR binding affinity - by increasing the molecular occupational volume near helix 12 of AR. In vitro, the analogues SK33 and SK51 showed very potent antiandrogenic activity, monitored using LNCaP/AR-Luciferase cells where growth, PSA and luciferase activity were used as AR activity measurements. These compounds were 10-fold more potent than bicalutamide and 100-fold more potent than enobosarm within the LNCaP model. These compounds were also active in LNCaP/BicR cells with acquired bicalutamide resistance. In vivo, using the AR-Luc reporter mice, these drugs showed potent AR inhibitory activity in the prostate and other AR-expressing tissues e.g. testes, seminal vesicles and brain. These compounds do not inhibit AR activity in the skeletal muscle, and spleen - thus indicating a selective tissue inhibitory profile. These compounds were also active in vivo in the Pb-PTen deletion model. SK33 and SK51 have significantly different and enhanced activity profiles compared to enobosarm, and are ideal candidates for further development for prostate cancer therapy with potentially fewer side effects.

Journal article

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