Robust-to-fragile transitions of a phase-separated mitotic organelle in triple-negative breast cancer

三阴性乳腺癌相分离有丝分裂细胞器的稳健到脆弱的转变

• 批准号: 10907877
• 负责人: P. TODD STUKENBERG
• 金额: $ 16.64万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10907877
• 关键词: Behavior; Cancer Model; Centromere; Chromosomes; Complex; Computer software; Diffusion; Feedback; Malignant Neoplasms; Metaphase; Microtubules; Mitotic; Modeling; Modification; Organelles; Phase; Phosphotransferases; Physical condensation; Physiological; Reaction; Research Project Grants; Route; Stress; Systems Analysis; Systems Biology; Time; Universities; Update; Virginia; histone modification; open source; recruit; repaired; triple-negative invasive breast carcinoma

Since the submission of U54-CA274499 (“Systems Analysis of Stress-adapted Cancer Organelles (SASCO) Center”), Research Project 1 at the University of Virginia has grown increasingly enthusiastic about co-opting these formalisms to enhance its study of “Robust-to-Fragile Transitions of a Phase-Separated Mitotic Organelle in Triple-Negative Breast Cancer”. We seek to build an experimentally constrained and physically grounded reaction-diffusion model of the regulatory network surrounding the chromosome passenger complex (CPC), which senses and repairs improper microtubule attachments during metaphase (11). The CPC is recruited bivalently to the inner centromere through a pair of orthogonal histone modifications that unfold within minutes. The modifications are each amplified by positive feedbacks involving a kinase subunit of the CPC. Together, these feedbacks are thought to promote all-or-nothing behavior depending on how spindle microtubules are attached. Project 1 co-lead Stukenberg discovered in 2019 that the non-kinase subunits of the CPC will form biomolecular condensates when increased above a critical concentration that is physiologically relevant (5). In the A0 submission, we described very rudimentary ideas for how the demixed CPC could be approximated stepwise through time-evolving compartments simulated in the open-source software VCell (12, 13). However, we had no clear route to initiating or updating demixed compartments in a principled way.

自提交U 54-CA 274499（“压力适应癌细胞器的系统分析”）以来， （SASCO）中心”），弗吉尼亚大学的研究项目1越来越热衷于 选择这些形式主义，以加强其研究“健壮的，以脆弱的转变相分离的有丝分裂 三阴性乳腺癌中的细胞器”。我们试图建立一个实验上受限制的， 染色体乘客复合体周围调控网络的接地反应扩散模型 (CPC)，其在中期期间感知并修复不适当的微管附着（11）。中国共产党是 通过一对正交的组蛋白修饰将双链体招募到内部着丝粒， 分钟每个修饰都通过涉及CPC的激酶亚基的正反馈来放大。 总之，这些反馈被认为是促进全有或全无的行为，这取决于主轴 微管被附着。项目1的共同负责人Stukenberg在2019年发现， CPC在增加到临界浓度以上时将形成生物分子缩合物， 生理相关（5）。在A0提交中，我们描述了非常基本的想法， CPC可以通过开源软件中模拟的时间演变分区逐步近似 软件VCell（12，13）。然而，我们没有明确的路线来启动或更新分层隔间， 有原则的方式。