Chromosomally unstable tumor cells specifically require KIF18A for proliferation.
Chromosomally unstable tumor cells specifically require KIF18A for proliferation.
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DOI：
10.1038/s41467-021-21447-2
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发表时间：
2021-02-22
影响因子：
16.6
通讯作者：
Stumpff J
中科院分区：
文献类型：
--
作者：
Marquis C;Fonseca CL;Queen KA;Wood L;Vandal SE;Malaby HLH;Clayton JE;Stumpff J
染色体不稳定性（CIN）是肿瘤细胞的一个标志，由微管的动力学和控制的变化引起，损害有丝分裂纺锤体。因此，CIN细胞对靶向有丝分裂纺锤体调节的治疗反应可能与二倍体细胞不同。在这里，我们通过抑制参与有丝分裂纺锤体控制的运动蛋白亚群来验证这一观点。KIF18A是来自三阴性乳腺癌或结直肠癌肿瘤的CIN细胞增殖所必需的，但在近二倍体细胞中不是必需的。在KIF18A抑制后，CIN肿瘤细胞表现出有丝分裂延迟、多极纺锤体和细胞死亡增加。对KIF18A敲低的敏感性与中心体分裂密切相关，中心体分裂需要动态微管，但不依赖于双极纺锤体形成或有丝分裂停止。我们的研究结果表明，CIN肿瘤细胞纺锤体微管动力学特性的改变可以用来降低CIN细胞的增殖能力。运动蛋白对维持有丝分裂纺锤体的完整性至关重要，这对染色体的稳定性至关重要。在这里，作者表明，运动蛋白KIF18A允许染色体不稳定细胞的增殖，而KIF18A的敲低诱导中心体断裂。
Chromosomal instability (CIN) is a hallmark of tumor cells caused by changes in the dynamics and control of microtubules that compromise the mitotic spindle. Thus, CIN cells may respond differently than diploid cells to treatments that target mitotic spindle regulation. Here, we test this idea by inhibiting a subset of kinesin motor proteins involved in mitotic spindle control. KIF18A is required for proliferation of CIN cells derived from triple negative breast cancer or colorectal cancer tumors but is not required in near-diploid cells. Following KIF18A inhibition, CIN tumor cells exhibit mitotic delays, multipolar spindles, and increased cell death. Sensitivity to KIF18A knockdown is strongly correlated with centrosome fragmentation, which requires dynamic microtubules but does not depend on bipolar spindle formation or mitotic arrest. Our results indicate the altered spindle microtubule dynamics characteristic of CIN tumor cells can be exploited to reduce the proliferative capacity of CIN cells. Kinesin motor proteins are critical for maintaining mitotic spindle integrity, which is important for chromosome stability. Here, the authors show that the kinesin motor protein, KIF18A, permits the proliferation of chromosomally unstable cells and knockdown of KIF18A induces centrosome fragmentation.
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影响因子：
2.7
作者：
Czechanski, Anne;Kim, Haein;Byers, Candice;Greenstein, Ian;Stumpff, Jason;Reinholdt, Laura G.
通讯作者：
Reinholdt, Laura G.
影响因子：
21.3
作者：
Bakhoum, Samuel F.;Thompson, Sarah L.;Manning, Amity L.;Compton, Duane A.
通讯作者：
Compton, Duane A.
染色体不稳定性通过胞质DNA反应驱动转移。
影响因子：
64.8
作者：
Bakhoum SF;Ngo B;Laughney AM;Cavallo JA;Murphy CJ;Ly P;Shah P;Sriram RK;Watkins TBK;Taunk NK;Duran M;Pauli C;Shaw C;Chadalavada K;Rajasekhar VK;Genovese G;Venkatesan S;Birkbak NJ;McGranahan N;Lundquist M;LaPlant Q;Healey JH;Elemento O;Chung CH;Lee NY;Imielenski M;Nanjangud G;Pe'er D;Cleveland DW;Powell SN;Lammerding J;Swanton C;Cantley LC
通讯作者：
Cantley LC
影响因子：
64.8
作者：
Cohen-Sharir Y;McFarland JM;Abdusamad M;Marquis C;Bernhard SV;Kazachkova M;Tang H;Ippolito MR;Laue K;Zerbib J;Malaby HLH;Jones A;Stautmeister LM;Bockaj I;Wardenaar R;Lyons N;Nagaraja A;Bass AJ;Spierings DCJ;Foijer F;Beroukhim R;Santaguida S;Golub TR;Stumpff J;Storchová Z;Ben-David U
通讯作者：
Ben-David U
影响因子：
9.2
作者：
Janssen, Louise M. E.;Averink, Tessa V.;Raaijmakers, Jonne A.
通讯作者：
Raaijmakers, Jonne A.