title: Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression.
abstract: Tissue-specific alternative splicing is critical for the emergence of tissue identity during development, yet the role of this process in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily conserved, alternative exons that represent only a minority of the total alternative exons identified. Many of these conserved exons have functional features that influence signaling pathways to profound biological effect. Here, we determined that lineage-specific splicing of a brain-enriched cassette exon in the membrane-binding tumor suppressor annexin A7 (ANXA7) diminishes endosomal targeting of the EGFR oncoprotein, consequently enhancing EGFR signaling during brain tumor progression. ANXA7 exon splicing was mediated by the ribonucleoprotein PTBP1, which is normally repressed during neuronal development. PTBP1 was highly expressed in glioblastomas due to loss of a brain-enriched microRNA (miR-124) and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that glioblastoma cells inherit the trait from a potential tumor-initiating ancestor and that these cells exploit this trait through accumulation of mutations that enhance EGFR signaling. Our data illustrate that lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates tumor suppressor functions and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ferrarese
authors.forename: Griffith R
authors.initials: GR
authors.lastname: Harsh
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Yadav
authors.forename: Eva
authors.initials: E
authors.lastname: Bug
authors.forename: Daniel
authors.initials: D
authors.lastname: Maticzka
authors.forename: Wilfried
authors.initials: W
authors.lastname: Reichardt
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Dombrowski
authors.forename: Tyler E
authors.initials: TE
authors.lastname: Miller
authors.forename: Anie P
authors.initials: AP
authors.lastname: Masilamani
authors.forename: Fangping
authors.initials: F
authors.lastname: Dai
authors.forename: Hyunsoo
authors.initials: H
authors.lastname: Kim
authors.forename: Michael
authors.initials: M
authors.lastname: Hadler
authors.forename: Denise M
authors.initials: DM
authors.lastname: Scholtens
authors.forename: Irene L Y
authors.initials: IL
authors.lastname: Yu
authors.forename: Jürgen
authors.initials: J
authors.lastname: Beck
authors.forename: Vinodh
authors.initials: V
authors.lastname: Srinivasasainagendra
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Costa
authors.forename: Nicoleta
authors.initials: N
authors.lastname: Baxan
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.forename: Dominik
authors.initials: D
authors.lastname: von Elverfeldt
authors.forename: Rolf
authors.initials: R
authors.lastname: Backofen
authors.forename: Astrid
authors.initials: A
authors.lastname: Weyerbrock
authors.forename: Christine W
authors.initials: CW
authors.lastname: Duarte
authors.forename: Xiaolin
authors.initials: X
authors.lastname: He
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.forename: James P
authors.initials: JP
authors.lastname: Chandler
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Arnab
authors.initials: A
authors.lastname: Chakravarti
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.forename: Maria S
authors.initials: MS
authors.lastname: Carro
authors.forename: Markus
authors.initials: M
authors.lastname: Bredel
mesh_terms: D017398:Alternative Splicing; D017310:Annexin A7 / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019070:Cell Lineage / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018450:Disease Progression; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005091:Exons; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics; D038941:Polypyrimidine Tract-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D017310:Annexin A7; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; C450006:PTBP1 protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D038941:Polypyrimidine Tract-Binding Protein; C512478:EGFR protein, human; D066246:ErbB Receptors