title: Resetting cancer stem cell regulatory nodes upon MYC inhibition.
abstract: MYC deregulation is common in human cancer and has a role in sustaining the aggressive cancer stem cell populations. MYC mediates a broad transcriptional response controlling normal biological programmes, but its activity is not clearly understood. We address MYC function in cancer stem cells through the inducible expression of Omomyc-a MYC-derived polypeptide interfering with MYC activity-taking as model the most lethal brain tumour, glioblastoma. Omomyc bridles the key cancer stemlike cell features and affects the tumour microenvironment, inhibiting angiogenesis. This occurs because Omomyc interferes with proper MYC localization and itself associates with the genome, with a preference for sites occupied by MYC This is accompanied by selective repression of master transcription factors for glioblastoma stemlike cell identity such as OLIG2, POU3F2, SOX2, upregulation of effectors of tumour suppression and differentiation such as ID4, MIAT, PTEN, and modulation of the expression of microRNAs that target molecules implicated in glioblastoma growth and invasion such as EGFR and ZEB1. Data support a novel view of MYC as a network stabilizer that strengthens the regulatory nodes of gene expression networks controlling cell phenotype and highlight Omomyc as model molecule for targeting cancer stem cells.
authors.affiliation: Biomedicine and Prevention Department, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Galardi
authors.affiliation: IBPM - CNR, Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Savino
authors.affiliation: IBPM - CNR, Rome, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Scagnoli
authors.affiliation: Molecular Neuro-Oncology Unit, Istituto Besta, Milan, Italy.|Experimental Oncology Department, IEO, Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Pellegatta
authors.affiliation: IFOM, the FIRC Institute for Molecular Oncology Foundation, and Cogentech, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Pisati
authors.affiliation: IBBE - CNR, Bari, Italy.|Biosciences Department, University of Milano, Milan, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Zambelli
authors.affiliation: IBPM - CNR, Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Illi
authors.affiliation: IBPM - CNR, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Annibali
authors.affiliation: IBPM - CNR, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Beji
authors.affiliation: Biomedicine and Prevention Department, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Orecchini
authors.affiliation: IBPM - CNR, Rome, Italy.
authors.forename: Maria Adele
authors.initials: MA
authors.lastname: Alberelli
authors.affiliation: IBPM - CNR, Rome, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Apicella
authors.affiliation: IBPM - CNR, Rome, Italy.
authors.forename: Rosaria Anna
authors.initials: RA
authors.lastname: Fontanella
authors.affiliation: Biomedicine and Prevention Department, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Michienzi
authors.affiliation: Molecular Neuro-Oncology Unit, Istituto Besta, Milan, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Finocchiaro
authors.affiliation: Biomedicine and Prevention Department, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Maria Giulia
authors.initials: MG
authors.lastname: Farace
authors.affiliation: Biosciences Department, University of Milano, Milan, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Pavesi
authors.affiliation: Biomedicine and Prevention Department, University of Rome Tor Vergata, Rome, Italy sergio.nasi@uniroma1.it ciafre@uniroma2.it.
authors.forename: Silvia Anna
authors.initials: SA
authors.lastname: Ciafrè
authors.affiliation: IBPM - CNR, Rome, Italy sergio.nasi@uniroma1.it ciafre@uniroma2.it.|Biology and Biotechnologies Department, Sapienza University, Rome, Italy.
authors.forename: Sergio
authors.identifier: 0000-0002-6744-2247
authors.initials: S
authors.lastname: Nasi
mesh_terms: D020533:Angiogenesis Inhibitors; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002454:Cell Differentiation; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D005909:Glioblastoma / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics; D000076104:Oligodendrocyte Transcription Factor 2; D010446:Peptide Fragments / Q000235:genetics*; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation; D059016:Tumor Microenvironment / Q000235:genetics; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D051792:Basic Helix-Loop-Helix Proteins; D066246:ErbB Receptors; D051796:Inhibitor of Differentiation Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D010446:Peptide Fragments; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D000071799:Zinc Finger E-box-Binding Homeobox 1; C490128:ID4 protein, human; C405708:OLIG2 protein, human; C486307:ZEB1 protein, human; C568271:omomyc protein; C512478:EGFR protein, human
keywords: MYC inhibition; gene networks; glioblastoma stem cells