title: Aneuploidy, oncogene amplification and epithelial to mesenchymal transition define spontaneous transformation of murine epithelial cells.
abstract: Human epithelial cancers are defined by a recurrent distribution of specific chromosomal aneuploidies, a trait less typical for murine cancer models induced by an oncogenic stimulus. After prolonged culture, mouse epithelial cells spontaneously immortalize, transform and become tumorigenic. We assessed genome and transcriptome alterations in cultures derived from bladder and kidney utilizing spectral karyotyping, array CGH, FISH and gene expression profiling. The results show widespread aneuploidy, yet a recurrent and tissue-specific distribution of genomic imbalances, just as in human cancers. Losses of chromosome 4 and gains of chromosome 15 are common and occur early during the transformation process. Global gene expression profiling revealed early and significant transcriptional deregulation. Chromosomal aneuploidy resulted in expression changes of resident genes and consequently in a massive deregulation of the cellular transcriptome. Pathway interrogation of expression changes during the sequential steps of transformation revealed enrichment of genes associated with DNA repair, centrosome regulation, stem cell characteristics and aneuploidy. Genes that modulate the epithelial to mesenchymal transition and genes that define the chromosomal instability phenotype played a dominant role and were changed in a directionality consistent with loss of cell adhesion, invasiveness and proliferation. Comparison with gene expression changes during human bladder and kidney tumorigenesis revealed remarkable overlap with changes observed in the spontaneously transformed murine cultures. Therefore, our novel mouse models faithfully recapitulate the sequence of genomic and transcriptomic events that define human tumorigenesis, hence validating them for both basic and preclinical research.
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. nashh@mail.nih.gov
authors.forename: Hesed M
authors.initials: HM
authors.lastname: Padilla-Nash
authors.forename: Nicole E
authors.initials: NE
authors.lastname: McNeil
authors.forename: Ming
authors.initials: M
authors.lastname: Yi
authors.forename: Quang-Tri
authors.initials: QT
authors.lastname: Nguyen
authors.forename: Yue
authors.initials: Y
authors.lastname: Hu
authors.forename: Danny
authors.initials: D
authors.lastname: Wangsa
authors.forename: David L
authors.initials: DL
authors.lastname: Mack
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Hummon
authors.forename: Chanelle
authors.initials: C
authors.lastname: Case
authors.forename: Eric
authors.initials: E
authors.lastname: Cardin
authors.forename: Robert
authors.initials: R
authors.lastname: Stephens
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Difilippantonio
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
mesh_terms: D000782:Aneuploidy; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism; D043171:Chromosomal Instability; D002869:Chromosome Aberrations; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D007668:Kidney / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009857:Oncogenes; D032681:Spectral Karyotyping / Q000379:methods; D014158:Transcription, Genetic; D059467:Transcriptome; D001743:Urinary Bladder / Q000166:cytology