• The interaction between CASK and the tumour suppressor Dlg1 regulates mitotic spindle orientation in mammalian epithelia

      Porter, Andrew P; White, Gavin RM; Mack, Natalie A; Malliri, Angeliki; Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield SK10 4TG, UK (2019)
      Oriented cell divisions are important for the formation of normal epithelial structures. Dlg1, a tumour suppressor, is required for mitotic spindle orientation in Drosophila epithelia and chick neuroepithelia, but how Dlg1 is localised to the membrane and its importance in mammalian epithelia are unknown. We show that Dlg1 is required in non-transformed mammalian epithelial cells for oriented cell divisions and normal lumen formation. We demonstrate that the MAGUK protein CASK, a membrane-associated scaffold, is the factor responsible for Dlg1 membrane localisation during spindle orientation, thereby identifying a new cellular function for CASK. Depletion of CASK leads to misoriented divisions in 3D, and to the formation of multilumen structures in cultured kidney and breast epithelial cells. Blocking the CASK-Dlg1 interaction with an interfering peptide, or by deletion of the CASK-interaction domain of Dlg1, disrupts spindle orientation and causes multilumen formation. We show that the CASK-Dlg1 interaction is important for localisation of the canonical LGN-NuMA complex known to be required for spindle orientation. These results establish the importance of the CASK-Dlg1 interaction in oriented cell division and epithelial integrity.This article has an associated First Person interview with the first author of the paper.
    • Trends in melanoma mortality in the population groups of South Africa

      Wright, CY; Kapwata, T; Singh, E; Green, Adele C; Baade, P; Kellett, P; Norval, M; Environment and Health Research Unit, South African Medical Research Council, Pretoria, South Africa (2019)
      The incidence of cutaneous melanoma (CM) is increasing in countries around the world. However, little is known about melanoma trends in African countries by population group. We studied CM mortality in South Africa from 1997 to 2014 to partly address this knowledge gap. Unit record mortality data for all South Africans who died from CM (n = 8,537) were obtained from Statistics South Africa. Join-point regression models were used to assess whether there was a statistically significant change in the direction and/or magnitude of the annual trends in CM mortality. A significant increasing trend of 11% per year was observed in age-adjusted mortality rates in men between 2000 and 2005 (p < 0.01), rising from 2 to 3 per 100,000. There was also a statistically significant increase of 180% per year among White South Africans from 1997 to 1999 (p < 0.05) and of 3% from 1999 to 2014 (p < 0.01). These results may be used to inform CM awareness campaigns and will motivate efforts to improve the collection and analysis of relevant statistics regarding the present burden of CM in South Africa.
    • Activating transcription factor ATF2 negatively regulates the expression of endothelial notch ligands

      Olivares, Ivonne; Kalyanakrishnan, Krithika; Ahmed, Suhail; Murcott, Clare; Wilkinson, Robert N; Cotton, James; Breitwieser, Wolfgang; Morris, Mark R; Armesilla, Angel L; RIHS, FSE, University of Wolverhampton (2019)
    • PARG inhibitors exhibit synthetic lethality with XRCC1 deficiency and a cellular mechanism of action that is distinct from PARP inhibition

      Martin, Leenus; Cheng, Tzuling; James, Dominic I; Begum, Habiba; Smith, Kate M; Jordan, Allan M; Waddell, Ian D; Vaidya, Kedar; Fischer, Marcus; Yao, Bing; et al. (2018)
    • Targeting PARG in pancreatic cancer: implications for synthetic lethal therapeutic strategies

      Chand, Saswati N; Ramirez, AnnJosette; Jain, Aditi; Nevler, Avinoam; Yabar-Lowder, Cinthya; Cozzitorto, Joseph A; James, Dominic I; Jordan, Allan M; Smith, Kate M; Waddell, Ian D; et al. (2018)
    • Novel small molecule inhibitors of p300/CBP down-regulate androgen receptor (AR) and c-Myc for the treatment of prostate cancer and beyond

      Pegg, Neil; Worthington, Jenny; Young, Barbara; Prosser, Amy; Gaughan, Luke; Spencer, Gary J; Somervaille, Tim CP; Burns, Julie; Knowles, Margaret; Brooks, Nigel; et al. (2018)
    • Poly (ADP) ribose glycohydrolase can be effectively targeted in pancreatic cancer

      Jain, A; Agostini, LC; McCarthy, GA; Chand, SN; Ramirez, A; Nevler, A; Cozzitorto, J; Schultz, CW; Lowder, CY; Smith, Kate M; et al. (2019)
      Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have an average survival of less than one year, underscoring the importance of evaluating novel targets with matched targeted agents. We recently identified that poly (ADP) ribose glycohydrolase (PARG) is a strong candidate target due to its dependence on the pro-oncogenic mRNA stability factor HuR (ELAVL1). Here, we evaluated PARG as a target in PDAC models using both genetic silencing of PARG and established small molecule PARG inhibitors, PDDX-001/004 (PARGi). Homologous repair-deficient cells compared to homologous repair-proficient cells were more sensitive to PARG inhibitors in vitro. In vivo, silencing of PARG significantly decreased tumor growth. PARGi synergized with DNA damaging agents (i.e., oxaliplatin and 5-FU), but not with PARP inhibitor therapy. Mechanistically, combined PARGi and oxaliplatin treatment led to persistence of detrimental PARylation, increased expression of cleaved caspase 3 and increased -H2AX foci. In summary, these data validate PARG as a relevant target in PDAC and establish current therapies that synergize with PARGi.
    • Discovery of selective, noncovalent small molecule inhibitors of DNMT1 as an alternative to traditional DNA hypomethylating agents

      Pappalardi, Melissa B; Cockerill, Mark J; Handler, Jessica L; Stowell, Alexandra IJ; Keenan, Kathryn; Sherk, Christian S; Minthorn, Elisabeth A; McHugh, Charles F; Burt, Charlotte; Wong, Kristen; et al. (2018)
    • Development of a screening cascade to identify selective small molecule inhibitors of DNMT1

      Stowell, Alexandra IJ; Thomson, Graeme J; Cockerill, Mark J; Burt, Charlotte; Fairweather, Emma E; Waddell, Ian D; Raoof, Ali; Jordan, Allan M; Ogilvie, Donald J; Pappalardi, Melissa; et al. (2018)
    • Genetic analysis of melanoma from an albino patient

      Bracalente, Candelaria; Mundra, Piyushkumar A; Rinflerch, Adriana; Garcia-Martinez, Pablo; Volonteri, Victoria; Trucco, Lucas D; Galimberti, Gaston; Dhomen, Nathalie; Pavet, Valeria R; Marais, Richard; et al. (2018)
    • Lysyl oxidase regulates cell surface EGFR, and directionality of cancer cell invasion

      Tang, Haoran; Springer, Caroline; Marais, Richard; CRUK Manchester Insitute, Manchester (2018)
    • Mitochondrial and ribosomal biogenesis are new hallmarks of stemness, oncometabolism and biomass accumulation in cancer: mito-stemness and ribo-stemness features

      Peiris-Pages, Maria; Ozsvari, B; Sotgia, F; Lisanti, MP; Clinical and Experimental Pharmacology, University of Manchester (2019)
      Using proteomics analysis, we previously compared MCF7 breast cancer cells grown as 3D tumor spheres, with the same cell line grown as monolayers. Our results indicated that during 3D anchorage-independent growth, the cellular machinery associated with i) mitochondrial biogenesis and ii) ribosomal biogenesis, were both significantly increased. Here, for simplicity, we refer to these two new oncogenic hallmarks as "mito-stemness" and "ribo-stemness" features. We have now applied this same type of strategy to begin to understand how fibroblasts and MCF7 breast cancer cells change their molecular phenotype, when they are co-cultured together. We have previously shown that MCF7-fibroblast co-cultures are a valuable model of resistance to apoptosis induced by hormonal therapies, such as Tamoxifen and Fulvestrant. Here, we directly show that these mixed co-cultures demonstrate the induction of mito-stemness and ribo-stemness features, likely reflecting a mechanism for cancer cells to increase their capacity for accumulating biomass. In accordance with the onset of a stem-like phenotype, KRT19 (keratin 19) was induced by ~6-fold during co-culture. KRT19 is a well-established epithelial CSC marker that is used clinically to identify metastatic breast cancer cells in sentinel lymph node biopsies. The potential molecular therapeutic targets that we identified by label-free proteomics of MCF7-fibroblast co-cultures were then independently validated using a bioinformatics approach. More specifically, we employed publically-available transcriptional profiling data derived from primary tumor samples from breast cancer patients, which were previously subjected to laser-capture micro-dissection, to physically separate breast cancer cells from adjacent tumor stroma. This allowed us to directly validate that the proteins up-regulated in this co-culture model were also transcriptionally elevated in patient-derived breast cancer cells in vivo. This powerful approach for target identification and translational validation, including the use of patient outcome data, can now be applied to other tumor types as well, to validate new therapeutic targets that are more clinically relevant, for patient benefit. Moreover, we discuss the therapeutic implications of these findings for new drug development, drug repurposing and Tamoxifen-resistance, to effectively target mito-stemness and ribo-stemness features in breast cancer patients. We also discuss the broad implications of this "organelle biogenesis" approach to cancer therapy.
    • Sunscreen photoprotection and vitamin D status

      Passeron, T; Bouillon, R; Callender, V; Cestari, T; Diepgen, TL; Green, Adele C; van der Pols, JC; Bernard, BA; Ly, F; Bernerd, F; et al. (2019)
      BACKGROUND: Global concern about vitamin D deficiency has fuelled debates on photoprotection and the importance of solar exposure to meet vitamin D requirements. OBJECTIVES: To review the published evidence to reach a consensus on the influence of photoprotection by sunscreens on vitamin D status, considering other relevant factors. METHODS: An international panel of 13 experts in endocrinology, dermatology, photobiology, epidemiology and biological anthropology reviewed the literature prior to a 1-day meeting in June 2017, during which the evidence was discussed. Methods of assessment and determining factors of vitamin D status, and public health perspectives were examined and consequences of sun exposure and the effects of photoprotection were assessed. RESULTS: A serum level of >/= 50 nmol L(-1) 25(OH)D is a target for all individuals. Broad-spectrum sunscreens that prevent erythema are unlikely to compromise vitamin D status in healthy populations. Vitamin D screening should be restricted to those at risk of hypovitaminosis, such as patients with photosensitivity disorders, who require rigorous photoprotection. Screening and supplementation are advised for this group. CONCLUSIONS: Sunscreen use for daily and recreational photoprotection does not compromise vitamin D synthesis, even when applied under optimal conditions.
    • Temporal stability and prognostic biomarker potential of the prostate cancer urine transcriptome

      Jeon, J; Olkhov-Mitsel, E; Xie, H; Yao, CQ; Zhao, F; Jahangiri, S; Cuizon, C; Scarcello, S; Jeyapala, R; Watson, JD; et al. (2019)
      BACKGROUND: To provide rapid evaluation of patients with advanced urological malignancies, a joint urological-oncological clinic was initiated at our institution in January 2015. We present the first 3-year evaluation of this joint urological-oncological clinic in Switzerland. METHOD: We performed a retrospective analysis of the characteristics and treatment of all patients reviewed at the joint clinic between January 2015 and December 2017. Statistical analysis was performed by survival analysis. A patient satisfaction questionnaire was handed out to new patients (from April to September 2017). RESULTS: A total of 135 new patients were counseled in the joint clinic and 563 consultations were performed in the period from January 2015 to December 2017. The majority were men with prostate cancer (85%), followed by bladder cancer (9%), and renal cell carcinoma (4%). Men with newly diagnosed metastatic prostate cancer (n = 69) received ADT alone (57%), ADT with docetaxel or abiraterone (33%), and metastasis-directed therapy (10%). High rates of patient satisfaction were reported based on the questionnaire. CONCLUSIONS: The joint clinic model has been successfully implemented at our institution and continues on a weekly basis. The clinic is increasingly used, not only for newly diagnosed metastatic prostate cancer, but also for other complex uro-oncological cases. The clinic allows optimized oncological treatment without delay and with a reduced effort for patients.
    • Frailty in older patients undergoing emergency laparotomy: results from the UK observational Emergency Laparotomy and Frailty (ELF) study

      Parmar, Kat; Law, J; Carter, B; Hewitt, J; Boyle, JM; Casey, P; Maitra, I; Farrell, IS; Pearce, L; Moug, SJ; et al. (2019)
      OBJECTIVE: This study aimed to document the prevalence of frailty in older adults undergoing emergency laparotomy and to explore relationships between frailty and postoperative morbidity and mortality. SUMMARY BACKGROUND DATA: The majority of adults undergoing emergency laparotomy are older adults (³65 y) that carry the highest mortality. Improved understanding is urgently needed to allow development of targeted interventions. METHODS: An observational multicenter (n=49) UK study was performed (March-June 2017). All older adults undergoing emergency laparotomy were included. Preoperative frailty score was calculated using the progressive Clinical Frailty Score (CFS): 1 (very fit) to 7 (severely frail). Primary outcome measures were the prevalence of frailty (CFS 5-7) and its association to mortality at 90 days postoperative. Secondary outcomes included 30-day mortality and morbidity, length of critical care, and overall hospital stay. RESULTS: A total of 937 older adults underwent emergency laparotomy: frailty was present in 20%. Ninety-day mortality was 19.5%. After age and sex adjustment, the risk of 90-day mortality was directly associated with frailty: CFS 5 adjusted odds ratio (aOR) 3.18 [95% confidence interval (CI), 1.24-8.14] and CFS 6/7 aOR 6á10 (95% CI, 2.26-16.45) compared with CFS 1. Similar associations were found for 30-day mortality. Increasing frailty was also associated with increased risk of complications, length of Intensive Care Unit, and overall hospital stay. CONCLUSIONS: A fifth of older adults undergoing emergency laparotomy are frail. The presence of frailty is associated with greater risks of postoperative mortality and morbidity and is independent of age. Frailty scoring should be integrated into acute surgical assessment practice to aid decision-making and development of novel postoperative strategies.
    • Phenotype plasticity as enabler of melanoma progression and therapy resistance

      Arozarena, I; Wellbrock, Claudia; Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Publica de Navarra (UPNA), Instituto de Investigacion Sanitaria de Navarra (IdiSNA), Pamplona, Spain (2019)
      Malignant melanoma is notorious for its inter- and intratumour heterogeneity, based on transcriptionally distinct melanoma cell phenotypes. It is thought that these distinct phenotypes are plastic in nature and that their transcriptional reprogramming enables heterogeneous tumours both to undergo different stages of melanoma progression and to adjust to drug exposure during treatment. Recent advances in genomic technologies and the rapidly expanding availability of large gene expression datasets have allowed for a refined definition of the gene signatures that characterize these phenotypes and have revealed that phenotype plasticity plays a major role in the resistance to both targeted therapy and immunotherapy. In this Review we discuss the definition of melanoma phenotypes through particular transcriptional states and reveal the prognostic relevance of the related gene expression signatures. We review how the establishment of phenotypes is controlled and which roles phenotype plasticity plays in melanoma development and therapy. Because phenotype plasticity in melanoma bears a great resemblance to epithelial-mesenchymal transition, the lessons learned from melanoma will also benefit our understanding of other cancer types.
    • Cysteine cathepsin protease inhibition: an update on its diagnostic, prognostic and therapeutic potential in cancer

      Soond, SM; Kozhevnikova, MV; Townsend, Paul A; Zamyatnin, AA; Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Trubetskaya str. 8-2, 119991 Moscow, Russia. (2019)
      In keeping with recent developments in basic research; the importance of the Cathepsins as targets in cancer therapy have taken on increasing importance and given rise to a number of key areas of interest in the clinical setting. In keeping with driving basic research in this area in a translational direction; recent findings have given rise to a number of exciting developments in the areas of cancer diagnosis; prognosis and therapeutic development. As a fast-moving area of research; the focus of this review brings together the latest findings and highlights the translational significance of these developments.
    • Letter to the editor in response to 'When to apply sunscreen: a consensus statement for Australia and New Zealand'

      Baldwin, L; Olsen, CM; Gordon, L; Green, Adele C; Aitken, J; Neale, R; Whiteman, D; Janda, M; Institute of Health and Biomedical Research, School of Public Health and Social Work, Faculty of Health, Queensland University of Technology, Australia (2019)
    • Author correction: Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data

      Rudin, CM; Poirier, JT; Byers, LA; Dive, Caroline; Dowlati, A; George, J; Heymach, JV; Johnson, JE; Lehman, JM; MacPherson, D; et al. (2019)
      An amendment to this paper has been published and can be accessed via a link at the top of the paper. Erratum for Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. [Nat Rev Cancer. 2019]
    • Histologic features associated with an invasive component in lentigo maligna lesions

      Moreno, A; Manrique-Silva, E; Viros, Amaya; Requena, C; Sanmartin, O; Traves, V; Nagore, E; School of Medicine, Universidad Catolica de Valencia San Vicente Martir, Valencia, Spain (2019)
      Importance: Lentigo maligna (LM) presents an invasive component in up to 20% of biopsied cases, but to date the histologic features useful in detecting this invasive component have not been described. Some histologic characteristics are hypothesized to contribute to the progression of LM invasion. Objective: To identify the histologic characteristics associated with lentigo maligna melanoma (LMM) in patients with LM diagnosed by a partial diagnostic biopsy. Design, Setting, and Participants: A retrospective cross-sectional study of patients treated between January 1, 2000, and December 31, 2017, was conducted in a referral oncology center in València, Spain. Data and specimens of patients (n?=?96) with a diagnosis of primary cutaneous melanoma in the form of either LM or LMM who had undergone surgical treatment, a complete histologic examination of the whole tumor, and an initial diagnostic partial biopsy of LM were included in the study. Histologic assessment was blinded to the presence of an invasive component. Interventions: All biopsy specimens were evaluated for the presence of certain histologic characteristics. Main Outcomes and Measures: Comparisons between invasive samples and samples without an invasive component were performed. The differences in the distribution of variables between the groups were assessed using the ?2 and Fisher exact tests, and the degree of association of the relevant variables was quantified by logistic regression models. A classification and regression tree analysis was performed to rank the variables by importance. Results: In total, 96 patients had sufficient histologic material that could be evaluated. The patients were predominantly male (56 [58.3%]) and had a mean (SD) age at diagnosis of 72 (12) years. Of these patients, 63 (65.6%) had an LM diagnosis and 33 (34.4%) had an LMM diagnosis (an invasive component). The histologic variables associated with the presence of an invasive component were melanocytes forming rows (odds ratio [OR], 11.5; 95% CI, 1.4-94.1; P?=?.02), subepidermal clefts (OR, 2.8; 95% CI, 1.0-7.9; P?=?.049), nests (OR, 3.0; 95% CI, 1.1-8.6; P?=?.04), and a lesser degree of solar elastosis (OR, 0.4; 95% CI, 0.1-1.1; P?=?.07). A classification and regression tree analysis of the relevant histologic features was able to accurately identify lentigo maligna with an invasive component (LMM) in more than 60% of patients. Conclusions and Relevance: These findings may be useful in classifying early LM specimens at higher risk of invasion, which may eventually be relevant in identifying the most appropriate management for LM.