TY - JOUR
T1 - Hybrids of aneuploid human cancer cells permit complementation of simple and complex cancer defects
AU - Dezentje, David A.
AU - Arking, Dan E.
AU - Kortenhorst, Madeleine S.Q.
AU - West, Kristen
AU - Chakravarti, Aravinda
AU - Kern, Scott E.
N1 - Funding Information:
NIH SPORE grant CA62924.
PY - 2009/2/15
Y1 - 2009/2/15
N2 - 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.
AB - 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.
KW - Aneuploidy
KW - Cancer
KW - Chromosomal instability
KW - Complementation
KW - Drug sensitivity
KW - Mitotic checkpoint
KW - Positional genetics
KW - Single-nucleotide polymorphisms
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U2 - 10.4161/cbt.8.4.7346
DO - 10.4161/cbt.8.4.7346
M3 - Article
C2 - 19305140
AN - SCOPUS:62549083898
SN - 1538-4047
VL - 8
SP - 347
EP - 355
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 4
ER -