title: Oncogenic Fusion Gene CD74-NRG1 Confers Cancer Stem Cell-like Properties in Lung Cancer through a IGF2 Autocrine/Paracrine Circuit.
abstract: The CD74-Neuregulin1 (NRG1) fusion gene was recently identified as novel driver of invasive mucinous adenocarcinoma, a malignant form of lung cancer. However, the function of the CD74-NRG1 fusion gene in adenocarcinoma pathogenesis and the mechanisms by which it may impart protumorigenic characteristics to cancer stem cells (CSC) is still unclear. In this study, we found that the expression of the CD74-NRG1 fusion gene increased the population of lung cancer cells with CSC-like properties. CD74-NRG1 expression facilitated sphere formation not only of cancer cells, but also of nonmalignant lung epithelial cells. Using a limiting dilution assay in a xenograft model, we further show that the CD74-NRG1 fusion gene enhanced tumor initiation. Mechanistically, we found that CD74-NRG1 expression promoted the phosphorylation of ErbB2/3 and activated the PI3K/Akt/NF-κB signaling pathway. Furthermore, the expression of the secreted insulin-like growth factor 2 (IGF2) and phosphorylation of its receptor, IGF1R, were enhanced in an NF-κB-dependent manner in cells expressing CD74-NRG1. These findings suggest that CD74-NRG1-induced NF-κB activity promotes the IGF2 autocrine/paracrine circuit. Moreover, inhibition of ErbB2, PI3K, NF-κB, or IGF2 suppressed CD74-NRG1-induced tumor sphere formation. Therefore, our study provides a preclinical rationale for developing treatment approaches based on these identified pathways to suppress CSC properties that promote tumor progression and recurrence.
authors.affiliation: Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan. Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan. Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Murayama
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakaoku
authors.affiliation: Division of Refractory Cancer Research, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Enari
authors.affiliation: Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Nishimura
authors.affiliation: Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Tominaga
authors.affiliation: Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Nakata
authors.affiliation: Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Arinobu
authors.initials: A
authors.lastname: Tojo
authors.affiliation: Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Sugano
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. ngotoh@ims.u-tokyo.ac.jp tkkohno@ncc.go.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.affiliation: Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan. Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan. ngotoh@ims.u-tokyo.ac.jp tkkohno@ncc.go.jp.
authors.forename: Noriko
authors.initials: N
authors.lastname: Gotoh
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics; D020890:Neuregulin-1 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C035170:IGF2 protein, human; D020890:Neuregulin-1; D007335:Insulin-Like Growth Factor II