Tissue stiffens in and around a tumor, making it clear that physical properties of a tissue change as tumors develop. While the genetic and biochemical events initiating cell transformation have been studied for decades, this proposal is aimed at expanding our knowledge of how, why, and to what extent physical environmental parameters, e.g. stiffness, drive tumor formation. Since these niche are dynamic, we have developed a model hydrogel system that stiffens ?on-demand? to understand the physical dynamics of cancer, i.e. methacrylated hyaluronic acid (MeHA) hydrogels. This material enables reductionist controlled unparalleled in most in vitro approaches and permits real time monitoring of mammary epithelial cells to observe their individual and collective responses to a changing environment in real time. MeHA hydrogels will be stiffened after the formation of mature acinar structures to determine how, why, and to what extent this induces the early stages of epithelial-to-mesenchymal transition (EMT). We will then determine whether this process is cell autonomous and how it couples with known inductive mechanisms, e.g. TGF-beta signaling. However significant heterogeneity exists in tumor initiation in vivo, and since our model offers a simple system in which to examine stiffness-induced EMT, in a second aim we will study whether EMT is caused by individual or collective decisions within the acinus. We will perform a detailed analysis of force transmission and mechanotransduction within acini, the MeHA hydrogel, and the surrounding basement membrane to dissect the molecular machinery used by individual or collections of cells to communicate and coordinate EMT. Finally we will test the roles of the identified EMT regulators in promoting tumor invasion and metastasis in vivo. This unique materials-based approach to EMT and malignant transformation, this proposal will significantly improve our understanding of EMT, its plasticity, and its regulators in vitro and apply it to an in vivo model.
Tumor progression starts in an otherwise soft niche but result in a stiff lump that a woman can actually feel. While we now appreciate that niche stiffness helps to drive tumor initiation, we have lacked the biomaterials to observe stiffening in vitro and to determine the pathways that drive tumor initiation. This proposal will leverage new biomaterials with cancer research to create synthetic environments that stiffen on-demand. This technology will enable careful, mechanistic exploration of stiffness' influence on mammary epithelial-to- mesenchymal transition in vitro and in vivo using intact mammary structures just at the onset of EMT.
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