Mechanobiology of Acinar Stability

腺泡稳定性的力学生物学

• 批准号: 8535645
• 负责人: Jan T. Liphardt
• 金额: $ 76.12万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8535645
• 关键词: Abnormal Cell; Accounting; Acinus organ component; Adhesions; Animals; Architecture; Basement membrane; Behavior; Biochemical; Biological Models; Blood Vessels; Breast; CD-ROM; Caliber; Cancer Diagnostics; Cancerous; Cell Survival; Cell model; Cells; Chemicals; Complex; Coupled; Cues; Development; Epithelial Cells; Estrogen Receptors; Extracellular Matrix; Generations; Genetic; Goals; Homeostasis; Hour; Laminin; Lead; Length; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mammary gland; Mechanical Stress; Mechanics; Modeling; Molecular and Cellular Biology; Normal Cell; Property; Role; Signal Transduction; Structure; System; Therapeutic; Time; Tissue Model; Tissues; Tubular formation; Tumor Tissue; behavior influence; cell behavior; cell growth; feeding; malignant breast neoplasm; migration; millimeter; millisecond; nanoscale; neoplastic cell; novel; physical science; pregnant; progesterone receptor negative; pup; research study; response; tool; transmission process; tumor; tumor progression

Mammary epithelial cells (MEC) are organized into tubular structures that terminate in end buds in the virgin animal but end in 'acini' in the mammary glands of pregnant and lactating animals. An acinus is a hollow, roughly spherical ball of cells with a diameter of -50 microns (see center diagram, above). An acinus consists of a single layer of polarized luminal epithelial cells surrounded by a layer of cells referred the as myoepithelium that interacts directly with a laminin-rich basement membrane. Once formed, an acinus is essentially 'stable' in the sense that its average composition, architecture, and size de net change with time until the animal steps feeding the pups. Why is it 'stable' and hew de a small number of specific biochemical and mechanical perturbations lead to less of this stability, and subsequently, malignant transformation? The maintenance of the acinar state involves constant biochemical and mechanical signaling on many length and time scales (nanometers the hundreds of microns; millisecond the hours and days). Some of this signaling involves the transmission of mechanical stresses through the entire acinus, which influences the behaviors of the cells that compose the acinus; these cells in turn can generate forces, which the propagate through the acinus. These forces are transmitted by cell-cell and cell-ECM adhesion. Disrupting the cellular force generation and sensing mechanisms promotes tumor formation [1, 2] (Levental et al. 2009, provided on CD-ROM appendix). A fundamental understanding of these tensional homeostasis mechanisms has broad implications for cancer, since tumor tissues are stiffer than normal and tumor cells show an aberrant response to force and demonstrate altered mechanical properties. These elevated forces and perturbed responsiveness the force enhance tumor cell growth and survival and promote their migration and invasion and even induce new blood vessel formation; all established hallmarks of tumors [1, 3]. The goal of Project 2 is to investigate the role of mechanical forces in acinar homeostasis. This is a tricky task, since forces would be acting on several length and time scales and all must be taken into account.

乳腺上皮细胞（MEC）组织成管状结构，在处女动物中终止于端芽，但在怀孕和哺乳动物的乳腺中终止于“腺泡”。腺泡是一个空心的、大致呈球形的细胞球，直径为 -50 微米（参见上面的中心图）。腺泡由单层极化的管腔上皮细胞组成，周围是一层称为肌上皮的细胞，肌上皮与富含层粘连蛋白的基底膜直接相互作用。一旦形成，腺泡本质上是“稳定的”，因为它的平均组成、结构和大小随着时间的推移而发生变化，直到动物开始喂养幼崽。为什么它是“稳定的”，并且少量特定的生化和机械扰动会导致这种稳定性降低，并随后导致恶性转化？腺泡状态的维持涉及许多长度和时间尺度（纳米到数百微米；毫秒到小时和天）的恒定生化和机械信号传导。其中一些信号涉及通过整个腺泡传递机械应力，这会影响组成腺泡的细胞的行为。这些细胞反过来可以产生力，并通过腺泡传播。这些力通过细胞-细胞和细胞-ECM 粘附传递。破坏细胞力的产生和传感机制会促进肿瘤形成 [1, 2]（Levental 等人，2009 年，在 CD-ROM 附录中提供）。对这些张力稳态机制的基本了解对癌症具有广泛的影响，因为肿瘤组织比正常组织更硬，并且肿瘤细胞对力表现出异常反应并表现出改变的机械特性。这些升高的力和扰乱的反应性增强了肿瘤细胞的生长和存活，促进其迁移和侵袭，甚至诱导新血管形成；所有已确定的肿瘤特征 [1, 3]。项目 2 的目标是研究机械力在腺泡稳态中的作用。这是一项棘手的任务，因为力会在多个长度和时间尺度上起作用，并且必须考虑所有因素。