Nuclear Dysfunction in Cancer: The Role of Mechanical Stresses Transmittedby the LINC Complex

癌症中的核功能障碍：LINC 复合体传递的机械应力的作用

• 批准号: 10571797
• 负责人: Tanmay P. Lele
• 金额: $ 56.52万
• 依托单位: TEXAS ENGINEERING EXPERIMENT STATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-06 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571797
• 关键词: 3-Dimensional; Address; Affect; Architecture; Binding; Biology; Breast Cancer Cell; Cancer Biology; Carcinoma; Cell Nucleus; Cell physiology; Cells; Cellular biology; Choristoma; Chromatin; Complex; Computer Models; Coupled; Cytoskeletal Modeling; Cytoskeleton; Data; Data Set; Development; Engineering; Epigenetic Process; Epithelial Cells; Epithelium; Functional disorder; Gene Abnormality; Gene Expression; Generations; Genes; Genome; Heterochromatin; Knowledge; Learning; Left; Malignant Neoplasms; Measures; Mechanical Stress; Mechanics; Membrane; Molecular; Molecular Biology; Mutate; Mutation; Normal Cell; Nuclear; Nuclear Envelope; Nuclear Lamina; Nuclear Structure; Pathogenesis; Phenotype; Positioning Attribute; Proteins; Role; Stress; Structure; System; breast cancer progression; cancer cell; cancer invasiveness; cell behavior; cell motility; driver mutation; env Gene Products; epigenomics; genome-wide; insight; malignant breast neoplasm; mammary epithelium; mechanical force; member; migration; multidisciplinary; novel strategies; physical science; protein complex; response; sensor; transmission process; virtual

PROJECT ABSTRACT The nuclear lamina is physically connected through nuclear envelope proteins to the cytoskeleton by the LINC complex (linker of nucleoskeleton to cytoskeleton), which spans the nuclear envelope and allows the transmission of mechanical forces to the nucleus. LINC complex proteins are frequently mutated or dysregulated in cancer, and some of these mutations have been proposed to be cancer drivers. Yet, how alterations to the LINC complex might promote cancer development is not known. This application's overarching hypothesis is that cytoskeletal force transmission to the nucleus is altered in cancer due to driver mutations in LINC proteins contributing to loss of epithelial polarity, aberrant tissue structure, abnormal gene expression, transformation and invasive cancer cell migration. The following aims are proposed: Aim 1. Define alterations to LINC complex- transmitted mechanical stresses in cancer. How the LINC complex transmits mechanical forces to position the nucleus and integrates tension in normal breast epithelia will be determined. The molecular and physical mechanisms for nuclear positioning in invasive breast epithelial cancer 3-D migration will be determined. Aim 2. Determine how the LINC complex contributes to altering the epigenetic organization of the genome during progression to breast cancer. The extent to which LINC disruption affects spatial partitioning of genes in the nucleus and heterochromatin organization will be identified; these effects will be correlated with cell phenotype, gene expression and epigenomic profiles. The requirement for an intact LINC complex for transformation to malignancy will be examined. The cancer nucleus remains highly understudied, with much to learn known about the physical principles that govern nuclear positioning, dysmorphia and chromatin organization, and how altered nuclear stresses contribute to cancer cell dysfunction. The focus of both aims is on the impact of cytoskeletal stresses transmitted by the LINC complex on gene expression and cell function. This necessarily requires an integrated understanding of both molecular and physical mechanisms. Extensive expertise gained in other systems will be coupled with new approaches for measuring forces on the nucleus. These include a direct force probe to interrogate nuclear mechanical responses in spread, living cells and nuclear tension sensors for the study of nuclear forces in both cancer and normal cells. Physically-based computational models will be used to interpret the resulting data. A physical approach will be applied to characterize the cancer nucleus and generate unique, genome-wide data sets for gene expression after experimentally altering LINC complex connections to discover the role of the LINC complex in breast cancer pathogenesis.

项目摘要 核纤层通过 LINC 通过核膜蛋白与细胞骨架物理连接 复合体（核骨架与细胞骨架的连接体），跨越核膜并允许 将机械力传递至原子核。 LINC 复合蛋白经常发生突变或失调 在癌症中，其中一些突变已被认为是癌症的驱动因素。然而，如何改变 LINC 复合物是否可能促进癌症发展尚不清楚。该应用程序的总体假设 由于 LINC 蛋白的驱动突变，癌症中向细胞核的细胞骨架力传递发生了改变 导致上皮极性丧失、组织结构异常、基因表达异常、转化和 侵袭性癌细胞迁移。提出以下目标： 目标 1. 定义对 LINC 复合体的改变- 在癌症中传递机械应力。 LINC 复合体如何将机械力传递到位置 将确定正常乳腺上皮细胞核和整合张力。分子和物理 将确定侵袭性乳腺上皮癌 3-D 迁移中核定位的机制。目标2。 确定 LINC 复合物如何有助于改变基因组的表观遗传组织 在进展为乳腺癌期间。 LINC 破坏影响基因空间分配的程度 在细胞核和异染色质组织中将被识别；这些影响将与细胞相关 表型、基因表达和表观基因组谱。完整的 LINC 复合体的要求 将检查是否转化为恶性肿瘤。癌核仍处于高度研究不足的状态，还有很多待研究的地方 了解控制核定位、畸形和染色质的物理原理 组织，以及改变的核应力如何导致癌细胞功能障碍。这两个目标的重点都是 关于 LINC 复合物传递的细胞骨架应激对基因表达和细胞功能的影响。 这必然需要对分子和物理机制的综合理解。广泛的 在其他系统中获得的专业知识将与测量原子核力的新方法相结合。 其中包括直接力探针，用于询问扩散、活细胞和细胞中的核机械反应。 核张力传感器用于研究癌细胞和正常细胞中的核力。基于物理的 计算模型将用于解释结果数据。将采用物理方法 表征癌症细胞核并生成独特的全基因组基因表达数据集 通过实验改变 LINC 复合体连接以发现 LINC 复合体在乳腺中的作用 癌症发病机制。