Agent-based modeling predicts RAC1 is critical for ovarian cancer metastasis.
Agent-based modeling predicts RAC1 is critical for ovarian cancer metastasis.
复制标题
DOI：
10.1091/mbc.e21-11-0540
复制
发表时间：
2022-12-01
影响因子：
3.3
通讯作者：
Grimes, Martha M.
中科院分区：
文献类型：
--
作者：
Rivera, Melanie;Toledo-Jacobo, Leslie;Romero, Elsa;Oprea, Tudor, I;Moses, Melanie E.;Hudson, Laurie G.;Wandinger-Ness, Angela;Grimes, Martha M.
实验和计算研究查明了由 Rac1 控制的转移中的限速步骤。使用卵巢癌细胞和动物模型，操纵 Rac1 表达，并对细胞与细胞和细胞与基质粘附、细胞侵袭、间皮清除和腹膜肿瘤生长进行定量测量，以区分受 Rac1 影响最大的肿瘤行为。实验数据用于参数化基于代理的计算模型，模拟腹膜微环境定植、内渗和远处器官的血行转移。 Rac1 过表达时更快速的粘附和内渗可增加卵巢癌细胞的存活率，预计会增加肿瘤细胞传播到远处部位的数量和速率。令人惊讶的是，无论 Rac1 是否过度表达或敲低，癌细胞沿血管的拥挤都会减少到达远处生态位的细胞数量，这表明肿瘤细胞内渗的部位受到速率限制，如果细胞快速内渗或由于活力降低而移位，则肿瘤细胞内渗的部位就变得容易接近。通过对 Rac1 依赖性肺转移的动物研究证实了模型预测。总的来说，实验和建模方法将细胞粘附、快速内渗和血液中的存活确定为卵巢转移级联中最关键依赖于 Rac1 的参数。
Experimental and computational studies pinpoint rate-limiting step(s) in metastasis governed by Rac1. Using ovarian cancer cell and animal models, Rac1 expression was manipulated, and quantitative measurements of cell–cell and cell–substrate adhesion, cell invasion, mesothelial clearance, and peritoneal tumor growth discriminated the tumor behaviors most highly influenced by Rac1. The experimental data were used to parameterize an agent-based computational model simulating peritoneal niche colonization, intravasation, and hematogenous metastasis to distant organs. Increased ovarian cancer cell survival afforded by the more rapid adhesion and intravasation upon Rac1 overexpression is predicted to increase the numbers of and the rates at which tumor cells are disseminated to distant sites. Surprisingly, crowding of cancer cells along the blood vessel was found to decrease the numbers of cells reaching a distant niche irrespective of Rac1 overexpression or knockdown, suggesting that sites for tumor cell intravasation are rate limiting and become accessible if cells intravasate rapidly or are displaced due to diminished viability. Modeling predictions were confirmed through animal studies of Rac1-dependent metastasis to the lung. Collectively, the experimental and modeling approaches identify cell adhesion, rapid intravasation, and survival in the blood as parameters in the ovarian metastatic cascade that are most critically dependent on Rac1.
影响因子：
3.9
作者：
Lou S;Wang P;Yang J;Ma J;Liu C;Zhou M
通讯作者：
Zhou M