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.

Public Health Relevance

By clarifying the basic principles by which adhesion-dependent mechano-chemicai cues modulate cellular signaling te modulate tissue development and homeostasis at multiple length scales, we anticipate identifying novel regulatory nodes that will permit the development ef alternative cancer diagnostics and therapeutics.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZCA1-SRLB-9)
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Stanford University
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