title: High rates of chromosome missegregation suppress tumor progression but do not inhibit tumor initiation.
abstract: Aneuploidy, an abnormal chromosome number that deviates from a multiple of the haploid, has been recognized as a common feature of cancers for >100 yr. Previously, we showed that the rate of chromosome missegregation/chromosomal instability (CIN) determines the effect of aneuploidy on tumors; whereas low rates of CIN are weakly tumor promoting, higher rates of CIN cause cell death and tumor suppression. However, whether high CIN inhibits tumor initiation or suppresses the growth and progression of already initiated tumors remained unclear. We tested this using the Apc(Min/+) mouse intestinal tumor model, in which effects on tumor initiation versus progression can be discriminated. Apc(Min/+) cells exhibit low CIN, and we generated high CIN by reducing expression of the kinesin-like mitotic motor protein CENP-E. CENP-E(+/-);Apc(Min/+) doubly heterozygous cells had higher rates of chromosome missegregation than singly heterozygous cells, resulting in increased cell death and a substantial reduction in tumor progression compared with Apc(Min/+) animals. Intestinal organoid studies confirmed that high CIN does not inhibit tumor cell initiation but does inhibit subsequent cell growth. These findings support the conclusion that increasing the rate of chromosome missegregation could serve as a successful chemotherapeutic strategy.
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705 Molecular and Cellular Pharmacology Training Program, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Zasadil
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705 Molecular and Cellular Pharmacology Training Program, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Eric M C
authors.initials: EM
authors.lastname: Britigan
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Sean D
authors.initials: SD
authors.lastname: Ryan
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Charanjeet
authors.initials: C
authors.lastname: Kaur
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: David J
authors.initials: DJ
authors.lastname: Guckenberger
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705 Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: David J
authors.initials: DJ
authors.lastname: Beebe
authors.affiliation: Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705 Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Moser
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705 Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705 baweaver@wisc.edu.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Weaver
mesh_terms: D000782:Aneuploidy; D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D043171:Chromosomal Instability / Q000235:genetics / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D020090:Chromosome Segregation / Q000235:genetics* / Q000502:physiology*; D002875:Chromosomes; D015179:Colorectal Neoplasms / Q000378:metabolism; D016547:Kinesins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D008941:Spindle Apparatus / Q000378:metabolism
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C068688:centromere protein E; D016547:Kinesins