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

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.

染色体不稳定性（Chromosomal instability, CIN）被定义为整条染色体频发丢失或获得的现象，是多数非整倍体实体瘤的标志性特征。CIN与患者不良预后及化疗耐药呈正相关。尽管其临床重要性不言而喻，但CIN在肿瘤起始、生长及/或进展中的作用仍有待深入阐明。迄今为止，用于解析CIN驱动肿瘤发生机制的唯一研究策略，均依托于刻意提升染色体错配率的转基因小鼠模型。本研究构建了一款转基因小鼠品系，其设计目标为定向降低染色体错配率并抑制CIN。该小鼠可轻度过表达驱动蛋白-13微管解聚酶Kif2b，这一策略已被证实可在体外培养体系中恢复人类癌细胞的精准染色体分离过程。借助LA2 K-Ras G12D诱导的肺癌模型，我们发现Kif2b表达可减少染色体分离缺陷的数量，但并未改变肺部肿瘤病灶的发生率。然而，表达Kif2b的小鼠体内的肺部肿瘤体积显著更大，且相较于对照组，此类肿瘤中Ki-67阳性细胞的比例显著升高。综上，在由K-Ras突变驱动的肺癌中，CIN对肿瘤起始几乎无影响，但可抑制肿瘤生长。上述数据支持如下模型：CIN会对肿瘤细胞施加生存负担，而提升有丝分裂保真度可加速肿瘤生长。