Hyper-active RAS/MAPK introduces cancer-specific mitotic vulnerabilities.
Hyper-active RAS/MAPK introduces cancer-specific mitotic vulnerabilities.
复制标题
过度活跃的 RAS/MAPK 会引入癌症特异性的有丝分裂漏洞。
DOI：
10.1073/pnas.2208255119
复制
发表时间：
2022-10-11
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
下一代癌症治疗剂将理想地抑制癌细胞独特需要的细胞活性，通常被称为对某种蛋白质的“成瘾”。为了实现这一目标，我们表明，虽然有丝分裂蛋白BubR 1是所需的纺锤体组装检查点在所有类型的细胞，其作用，在稳定kinetochore-microtubule附件往往是不稳定的。我们发现，相对于非转化细胞，RAS/MAPK信号放大的肿瘤细胞表现出增强的BubR 1的要求，以在有丝分裂过程中对齐染色体，并防止致命的染色体分离错误。总之，这项工作扩展了我们对染色体分离和癌症生物学如何交叉的理解，并强调了探索不同细胞状态下有丝分裂过程的必要性。非整倍性，即不正确的完整染色体数目，是肿瘤的常见特征，有助于肿瘤的发生和发展。防止非整倍体需要功能正常的动粒，动粒是在着丝粒DNA上组装的大蛋白质复合物，其将有丝分裂染色体连接到动态纺锤体微管并促进染色体分离。动粒利用至少两种机制来防止非整倍性：纠错和纺锤体组装检查点（SAC）。BubR 1是参与这两个过程的一个因子，被确定为多种肿瘤类型的癌症依赖性和治疗靶点;然而，目前尚不清楚是什么特定的致癌压力驱动了这种对BubR 1的增强依赖性，以及它是否源于BubR 1对SAC或纠错途径的调节。在这里，我们使用遗传控制的转化模型和胶质母细胞瘤肿瘤分离株，以表明RAS或MAPK的组成性信号传导是癌症特异性BubR 1脆弱性所必需的。MAPK途径酶促过度刺激一个着丝粒激酶网络，损害染色体分离，使细胞更依赖于两个BubR 1活动：抵消过度的着丝粒微管周转错误校正和维持SAC。这项工作扩展了我们对染色体分离如何适应不同细胞状态的理解，并揭示了癌症特异性缺陷的致癌触发因素。
The next generation of cancer therapeutics will ideally inhibit cellular activities that are uniquely required by cancer cells, often referred to as an “addiction” to a certain protein. Toward this goal, we show that, while the mitotic protein BubR1 is required for the spindle assembly checkpoint in all cell types, its role in stabilizing kinetochore–microtubule attachments is often dispensable. We find that, relative to nontransformed cells, tumor cells with amplified RAS/MAPK signaling exhibit an enhanced requirement for BubR1 to align chromosomes during mitosis and prevent lethal chromosome segregation errors. Altogether, this work expands our understanding of how chromosome segregation and cancer biology intersect and highlights the need to explore mitotic processes in diverse cellular states. Aneuploidy, the incorrect number of whole chromosomes, is a common feature of tumors that contributes to their initiation and evolution. Preventing aneuploidy requires properly functioning kinetochores, which are large protein complexes assembled on centromeric DNA that link mitotic chromosomes to dynamic spindle microtubules and facilitate chromosome segregation. The kinetochore leverages at least two mechanisms to prevent aneuploidy: error correction and the spindle assembly checkpoint (SAC). BubR1, a factor involved in both processes, was identified as a cancer dependency and therapeutic target in multiple tumor types; however, it remains unclear what specific oncogenic pressures drive this enhanced dependency on BubR1 and whether it arises from BubR1’s regulation of the SAC or error-correction pathways. Here, we use a genetically controlled transformation model and glioblastoma tumor isolates to show that constitutive signaling by RAS or MAPK is necessary for cancer-specific BubR1 vulnerability. The MAPK pathway enzymatically hyperstimulates a network of kinetochore kinases that compromises chromosome segregation, rendering cells more dependent on two BubR1 activities: counteracting excessive kinetochore–microtubule turnover for error correction and maintaining the SAC. This work expands our understanding of how chromosome segregation adapts to different cellular states and reveals an oncogenic trigger of a cancer-specific defect.
登录
查看更多内容
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.
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：
3.7
作者：
Harris, L;Davenport, J;Goorha, R
通讯作者：
Goorha, R
影响因子：
64.8
作者：
Cahill, DP;Lengauer, C;Vogelstein, B
通讯作者：
Vogelstein, B
DOI：
10.1073/pnas.0401142101
发表时间：
2004-06-08
影响因子：
11.1
作者：
Kops, GJPL;Foltz, DR;Cleveland, DW
通讯作者：
Cleveland, DW