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Targeting kinetochore-microtubule stability affects chromosome segregation and tumor growth in mice / by Christopher D. Laucius

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Author	Laucius, Christopher D.
Title	Targeting kinetochore-microtubule stability affects chromosome segregation and tumor growth in mice / by Christopher D. Laucius
Date	2016
Abstract	Chromosomal instability (CIN) is defined as a high rate of whole chromosome loss or gain and is a hallmark of many aneuploid solid tumors. CIN positively correlates with poor patient prognosis and chemotherapeutic resistance. The persistence of mal-oriented attachments of spindle microtubules to kinetochores during mitosis is the most common cause of CIN. Correction of these mal-orientations relies on detachment of microtubules from kinetochores, a process that is directly affected by the stability of kinetochore-microtubule (kMT) attachments. Despite its clinical importance, the role of CIN in tumor initiation, growth and/or progression remains poorly understood. To date, the only strategies developed to determine how CIN contributes to tumorigenesis have relied on transgenic mouse models that deliberately increase the rate of chromosomal mis-segregation. Here I describe a novel strain of transgenic mice that is designed to strategically decrease the rate of chromosome mis-segregation and suppress CIN by altering kMT stability. These animals modestly overexpress the kinesin-13 microtubule depolymerase Kif2b, a strategy proven successful in restoring faithful chromosome segregation to human cancer cells in culture. Embryonic fibroblasts derived from mice overexpressing Kif2b display fewer chromosome segregation defects relative to non-transgenic littermates confirming the efficacy of this strategy in live animals. Using the LA2 K-Ras G12D-induced model for lung cancer, I show that Kif2b expression does not change the incidence of lung tumor lesions. However, pulmonary tumors were significantly larger in animals expressing Kif2b and relative to controls. Thus, in lung cancers driven by mutations in K-Ras, CIN has little impact on tumor initiation but suppresses tumor growth. These data support a model in which CIN imposes a burden on tumor cells, and that enhancement of mitotic fidelity results in accelerated tumor growth. Furthermore, is has been shown overexpression of kMT stabilizers or loss of destabilizers induces CIN. Using low doses of the microtubule drug Taxol, I demonstrate that pharmacological stabilization of kMT stability can drive chromosome mis-segregation in both cell culture in vitro and in mouse intestinal epithelium in vivo.
Description	1 online resource (xiii, 167 leaves) : illustrations (some color)
Format	application/pdf
College	Geisel School of Medicine at Dartmouth -- Department of Biochemistry.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D)--Dartmouth College.
Copyright	Made available by the author under a Creative Commons Attribution-NonCommercial License.; Made available by the Trustees of Dartmouth College under a Creative Commons Attribution-NonCommercial License. https://creativecommons.org/licenses/by-nc/4.0/
DOI	https://doi.org/10.1349/ddlp.2257

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Targeting kinetochore-microtubule stability affects chromosome segregation and tumor growth in mice / by Christopher D. Laucius

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