Mechanobiology of Acinar Stability

乳腺上皮细胞（MEC）被组织成管状结构，在处女动物中终止于端芽，但在妊娠和哺乳动物的乳腺中终止于“腺泡”。腺泡是一个中空的，大致球形的细胞球，直径约为50微米（见上图中心）。腺泡由单层极化的腔上皮细胞组成，腔上皮细胞被称为肌上皮的细胞层包围，肌上皮直接与富含层粘连蛋白的基底膜相互作用。一旦形成，腺泡基本上是“稳定的”，在这个意义上，它的平均组成，结构和净大小随着时间的推移而变化，直到动物开始喂养幼崽。为什么它是“稳定的”，而少数特定的生化和机械扰动导致这种稳定性降低，并随后发生恶性转化？腺泡状态的维持涉及许多长度和时间尺度上的恒定生化和机械信号（纳米是数百微米;毫秒是小时和天）。其中一些信号涉及机械应力通过整个腺泡的传递，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，这些力通过腺泡传播。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感知机制会促进肿瘤形成[1，2]（Levental等人，2009，在CD-ROM附录中提供）。对这些张力稳态机制的基本理解对癌症具有广泛的意义，因为肿瘤组织比正常组织更硬，肿瘤细胞对力表现出异常反应，并表现出改变的机械特性。这些升高的力和扰动的响应力增强了肿瘤细胞的生长和存活，促进了它们的迁移和侵袭，甚至诱导了新血管的形成;所有这些都是肿瘤的既定标志[1，3]。项目2的目标是研究机械力在腺泡稳态中的作用。这是一个棘手的任务，因为力将在几个长度和时间尺度上作用，所有这些都必须考虑在内。

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.