Hybrids of aneuploid human cancer cells permit complementation of simple and complex cancer defects

David A. Dezentje, Dan E. Arking, Madeleine S.Q. Kortenhorst, Kristen West, Aravinda Chakravarti, Scott E. Kern

Research output: Contribution to journalArticle

Abstract

Causes for the complex phenotypes of cancers, such as altered differentiation, invasion and metastasis, are not known, and multigenic defects are likely. In contrast, well-defined deficiencies, such as those affecting DNA-repair mechanisms and enzymatic pathways, are simple, typically caused by one or a few gene mutations. Complementation by introducing defined genetic elements is used to study simple cancer phenotypes, while complementation by the fusion of whole cells is employed occasionally for complex ones. Hybrids formed solely from the common lines (aneuploid due to chromosomal instability, CIN) are rarely reported. We created stable hybrids of two CIN lines, producing a nearly complete genetic sum of the parental karyotypes. Complementation of a simple cancer phenotype, a Fanconi anemia pathway defective in both parental lines, occurred in all hybrids, restoring the normal drug-resistance phenotype. The grossly defective mitotic spindle checkpoint present in both parental lines was partially corrected in some hybrids, supporting a multigenic origin rather than a single gene defect. Using Affymetrix 100K SNP chips, we mapped chromosomal loci differing among the phenotypically distinct hybrid clones. Fusing CIN cell lines to form mapped hybrids offers new tools for positional cloning or classification of simple and complex cancer phenotypes, including mechanical defects and altered drug responses.

Original languageEnglish (US)
Pages (from-to)347-355
Number of pages9
JournalCancer Biology and Therapy
Volume8
Issue number4
DOIs
StatePublished - Feb 15 2009

Keywords

  • Aneuploidy
  • Cancer
  • Chromosomal instability
  • Complementation
  • Drug sensitivity
  • Mitotic checkpoint
  • Positional genetics
  • Single-nucleotide polymorphisms

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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