Chromosomal instability suppresses the growth of K-Ras-induced lung adenomas.

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. Despite this 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 we develop a strain of transgenic mice that is designed to strategically decrease the rate of chromosome mis-segregation and suppress CIN. 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. Using the LA2 K-Ras G12D-induced model for lung cancer, we show that Kif2b expression reduces the number of chromosome segregation defects but does not change the incidence of lung tumor lesions. However, pulmonary tumors were significantly larger in animals expressing Kif2b and those tumors exhibited elevated rates of Ki-67 positive cells 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.

SUBMITTER: Laucius CD 

PROVIDER: S-EPMC6649550 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature