Now showing 1 - 7 of 7
  • Publication
    Integrating network reconstruction with mechanistic modeling to predict cancer therapies
    (American Association for the Advancement of Science, 2016-11-22) ; ; ;
    Signal transduction networks (STNs) are often rewired in cancerous cells. Effective cancer treatment requires identifying and repairing these harmful alterations. We developed a computational framework which can identify these aberrations and predict potential targets for intervention. It reconstructs network models of STNs from noisy and incomplete perturbation response data, and then uses the reconstructed networks to develop mechanistic models of STNs for predicting potential treatments. As a proof of principle, we analysed a perturbation dataset targeting Epidermal Growth Factor Receptor (EGFR) and Insulin like 2 Growth Factor 1 Receptor (IGF1R) pathways in a panel of colorectal cancer (CRC) cells, revealing cell line specific STN rewiring. Specifically, we found that the feedback inhibition of IRS1 by p70S6K is associated with resistance to EGF receptor (EGFR) inhibition, and disrupting this feedback may restore sensitivity to EGFR inhibitors in CRC cells. These findings were experimentally validated in vitro and in zebrafish (Danio rerio) xenografts.
      737Scopus© Citations 49
  • Publication
    Signaling pathway models as biomarkers: Patient-specific simulations of JNK activity predict the survival of neuroblastoma patients
    Signaling pathways control cell fate decisions that ultimately determine the behavior of cancer cells. Therefore, the dynamics of pathway activity may contain prognostically relevant information different from that contained in the static nature of other types of biomarkers. To investigate this hypothesis, we characterized the network that regulated stress signaling by the c-Jun N-terminal kinase (JNK) pathway in neuroblastoma cells. We generated an experimentally calibrated and validated computational model of this network and used the model to extract prognostic information from neuroblastoma patient–specific simulations of JNK activation. Switch-like JNK activation mediates cell death by apoptosis. An inability to initiate switch-like JNK activation in the simulations was significantly associated with poor overall survival for patients with neuroblastoma with or without MYCN amplification, indicating that patient-specific simulations of JNK activation could stratify patients. Furthermore, our analysis demonstrated that extracting information about a signaling pathway to develop a prognostically useful model requires understanding of not only components and disease-associated changes in the abundance or activity of the components but also how those changes affect pathway dynamics.
      1395Scopus© Citations 111
  • Publication
    Wnt signalling is a bi-directional vulnerability of cancer cells
    Wnt signalling is involved in the formation, metastasis and relapse of a wide array of cancers. However, there is ongoing debate as to whether activation or inhibition of the pathway holds the most promise as a therapeutic treatment for cancer, with conflicting evidence from a variety of tumour types. We show that Wnt/β-catenin signalling is a bi-directional vulnerability of neuroblastoma, malignant melanoma and colorectal cancer, with hyper-activation or repression of the pathway both representing a promising therapeutic strategy, even within the same cancer type. Hyper-activation directs cancer cells to undergo apoptosis, even in cells oncogenically driven by β-catenin. Wnt inhibition blocks proliferation of cancer cells and promotes neuroblastoma differentiation. Wnt and retinoic acid co-treatments synergise, representing a promising combination treatment for MYCN-amplified neuroblastoma. Additionally, we report novel cross-talks between MYCN and β-catenin signalling, which repress normal β-catenin mediated transcriptional regulation. A β-catenin target gene signature could predict patient outcome, as could the expression level of its DNA binding partners, the TCF/LEFs. This β-catenin signature provides a tool to identify neuroblastoma patients likely to benefit from Wnt-directed therapy. Taken together, we show that Wnt/β-catenin signalling is a bi-directional vulnerability of a number of cancer entities, and potentially a more broadly conserved feature of malignant cells.
      455Scopus© Citations 27
  • Publication
    Integrative omics reveals MYCN as a global suppressor of cellular signalling and enables network-based therapeutic target discovery in neuroblastoma
    Despite intensive study, many mysteries remain about the MYCN oncogene's functions. Here we focus on MYCN's role in neuroblastoma, the most common extracranial childhood cancer. MYCN gene amplification occurs in 20% of cases, but other recurrent somatic mutations are rare. This scarcity of tractable targets has hampered efforts to develop new therapeutic options. We employed a multi-level omics approach to examine MYCN functioning and identify novel therapeutic targets for this largely un-druggable oncogene. We used systems medicine based computational network reconstruction and analysis to integrate a range of omic techniques: sequencing-based transcriptomics, genome-wide chromatin immunoprecipitation, siRNA screening and interaction proteomics, revealing that MYCN controls highly connected networks, with MYCN primarily supressing the activity of network components. MYCN's oncogenic functions are likely independent of its classical heterodimerisation partner, MAX. In particular, MYCN controls its own protein interaction network by transcriptionally regulating its binding partners.Our network-based approach identified vulnerable therapeutically targetable nodes that function as critical regulators or effectors of MYCN in neuroblastoma. These were validated by siRNA knockdown screens, functional studies and patient data. We identified β-estradiol and MAPK/ERK as having functional cross-talk with MYCN and being novel targetable vulnerabilities of MYCN-amplified neuroblastoma. These results reveal surprising differences between the functioning of endogenous, overexpressed and amplified MYCN, and rationalise how different MYCN dosages can orchestrate cell fate decisions and cancerous outcomes. Importantly, this work describes a systems-level approach to systematically uncovering network based vulnerabilities and therapeutic targets for multifactorial diseases by integrating disparate omic data types.
      395Scopus© Citations 30
  • Publication
    Moving Away from Solely MCQ-based Exams: Short Answer Questions for Enhancing the Variety of Assessment Methods in the Large Classroom
    (Access and Lifelong Learning, University College Dublin, 2019-05-29)
    PATH30030 Haematology/Immunosuppression is a UCD level 3 (NFQ level 8) Pathology module in Medicine worth 5.0 ECTS credits. The module is designed for the combined cohort of Stage 2 Graduate Entry Medicine (GEM) and Stage 4 Undergraduate Medicine (UgM) Programmes (including a group of Malaysian students) for the maximum number of 315 students, from all over the world. The students have diverse educational, cultural and ethnic backgrounds. 190 This module outlines the diseases of the peripheral blood, bone marrow and lymph nodes and their treatment. It includes the principles of transfusion, the study of infective agents seen in the immunocompromised patient, helminths and infections seen in the returned traveller and their treatment. Pathology, Medical Microbiology and Pharmacology contents are delivered in this module by academic staff and clinicians. Previously, the assessment on this module was purely multiple-choice question (MCQ) based end-of-semester examination (N=90; 100% of module grade) (Table 1). In Medicine, MCQ based examinations are favoured because they enable assessment of large amounts of content/knowledge, and it is possible to grade them by computer (and generate associated statistics) (Epstein, 2007; Table 2). The latter is especially beneficial if large numbers of students are enrolled to the programme. However, MCQs cannot assess problem-solving ability and clinical reasoning skills which medical students need to develop. In addition, students might guess the correct answer reinforcing false knowledge. Student feedback revealed that students do not like the pure MCQ based examinations, and suggested including some element of continuous assessment, and a written part to the exit exam. The student feedback also indicated that they would learn more if there was a written part to the exam.
  • Publication
    Progesterone-induced blocking factor differentially regulates trophoblast and tumor invasion by altering matrix metalloproteinase activity
    Invasiveness is a common feature of trophoblast and tumors; however, while tumor invasion is uncontrolled, trophoblast invasion is strictly regulated. Both trophoblast and tumor cells express high levels of the immunomodulatory progesterone-induced blocking factor (PIBF), therefore, we aimed to test the possibility that PIBF might be involved in invasion. To this aim, we used PIBF-silenced or PIBF-treated trophoblast (HTR8/Svneo, and primary trophoblast) and tumor (HT-1080, A549, HCT116, PC3) cell lines. Silencing of PIBF increased invasiveness as well as MMP-2,-9 secretion of HTR8/SVneo, and decreased those of HT-1080 cells. PIBF induced immediate STAT6 activation in both cell lines. Silencing of IL-4Rα abrogated all the above effects of PIBF, suggesting that invasion-related signaling by PIBF is initiated through the IL-4Rα/PIBF-receptor complex. In HTR-8/SVneo, PIBF induced fast, but transient Akt and ERK phosphorylation, whereas in tumor cells, PIBF triggered sustained Akt, ERK, and late STAT3 activation. The late signaling events might be due to indirect action of PIBF. PIBF induced the expression of EGF and HB-EGF in HT-1080 cells. The STAT3-activating effect of PIBF was reduced in HB-EGF-deficient HT-1080 cells, suggesting that PIBF-induced HB-EGF contributes to late STAT3 activation. PIBF binds to the promoters of IL-6, EGF, and HB-EGF; however, the protein profile of the protein/DNA complex is different in the two cell lines. We conclude that in tumor cells, PIBF induces proteins, which activate invasion signaling, while—based on our previous data—PIBF might control trophoblast invasion by suppressing proinvasive genes.
      642Scopus© Citations 51
  • Publication
    The role of progesterone in implantation and trophoblast invasion
    With its genomic and non-genomic actions, progesterone plays a role in preparing the endometrium for implantation and also in regulating trophoblast invasion and migration. The genomic actions of progesterone are mediated by the classical nuclear progesterone receptors, PR-A and PR-B. In addition to their genomic actions, nuclear progesterone receptors may also trigger rapid cytoplasmic signalling events. Membrane-bound progesterone receptors have been implicated in the rapid non-genomic actions of progesterone. Both genomic and extra-nuclear actions of progesterone are crucial for adequate decidualisation and implantation. Progesterone plays a role in establishing uterine receptivity by blocking the proliferative effect of oestrogen, by inducing genes that allow the endometrium to permit embryo attachment, and also acts as a negative regulator of trophoblast invasion by controlling matrix metalloproteinase (MMP) activity.
      1346Scopus© Citations 92