The central hypothesis of Project I is that the spatial organization of signaling proteins is actively altered by mechanical forces and this provides a molecular scale mechanism for physical forces to directly regulate chemical signaling in cancer. The long-term goal of this proposal is tee develop a molecular level understanding of how mechanical forces can exert regulatory control over chemical signaling processes. We seek a fundamental understanding of hew the mechanical environment of a cell influences its intracellular chemical signaling. Te achieve this goal, we propose a highly multidisciplinary. hybrid physical and biological approach aimed at deconstructing how key chemical signal transduction pathways of significance in cancer can be responsive to mechanical inputs. The rationale for this is that the spatial organization of signaling proteins is altered in the different phases leading tee malignancy, and this is fundamentally net a chemical mutation in the structure of a protein, but rather a physical perturbation of protein organization on the macromolecular length scale (7, 2). The premise of our approach is that characterizing and controlling mechanical forces that drive receptor organization will allow us to elicit structural and functional phenotypes characteristic of defined phases of in cancer progression. We will target the EphA2 receptor signaling pathway as well as the Ras signaling module. These are chosen for their emerging roles in chemomechanical signal transduction. We will implement a combined approach that consists of 1) super-resolution imaging of hybrid cell-supported membrane junctions, 2) micro cantilever-based lateral force measurements of ligand-functionalized probes, and 3) nanoscissor laser surgery for cytoskeletal disruption. All three of these approaches will be employed in the context of the newly developed spatial mutation strategy, which provides unique opportunities tee mechanically perturb living cells with chemical specificity. Mathematical modeling is an essential part of all quantitative investigations and is integrated here as well.
The major cause of death in cancer is from malignant cells that act through mechanisms that can be mechanical. We currentiy have no approved drugs that target this fundamental process. The proposed research provides the potential to discover a new class of therapeutics that will alter mechano-transduction and inhibit or reduce malignant behavior.
|Damiano, L; Stewart, K M; Cohet, N et al. (2014) Oncogenic targeting of BRM drives malignancy through C/EBP*-dependent induction of *5 integrin. Oncogene 33:2441-53|
|Veiseh, Mandana; Kwon, Daniel H; Borowsky, Alexander D et al. (2014) Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset. Proc Natl Acad Sci U S A 111:E1731-9|
|Kim, Yushan; Kumar, Sanjay (2014) CD44-mediated adhesion to hyaluronic acid contributes to mechanosensing and invasive motility. Mol Cancer Res 12:1416-29|
|Venugopalan, Gautham; Camarillo, David B; Webster, Kevin D et al. (2014) Multicellular architecture of malignant breast epithelia influences mechanics. PLoS One 9:e101955|
|Shi, Quanming; Ghosh, Rajarshi P; Engelke, Hanna et al. (2014) Rapid disorganization of mechanically interacting systems of mammary acini. Proc Natl Acad Sci U S A 111:658-63|
|Greene, Adrienne C; Lord, Samuel J; Tian, Aiwei et al. (2014) Spatial organization of EphA2 at the cell-cell interface modulates trans-endocytosis of ephrinA1. Biophys J 106:2196-205|
|Hines, William C; Su, Ying; Kuhn, Irene et al. (2014) Sorting out the FACS: a devil in the details. Cell Rep 6:779-81|
|Nickerson, Andrew; Huang, Tao; Lin, Li-Jung et al. (2014) Photoactivated localization microscopy with bimolecular fluorescence complementation (BiFC-PALM) for nanoscale imaging of protein-protein interactions in cells. PLoS One 9:e100589|
|MacKay, Joanna L; Sood, Anshum; Kumar, Sanjay (2014) Three-dimensional patterning of multiple cell populations through orthogonal genetic control of cell motility. Soft Matter 10:2372-80|
|Paszek, Matthew J; DuFort, Christopher C; Rossier, Olivier et al. (2014) The cancer glycocalyx mechanically primes integrin-mediated growth and survival. Nature 511:319-25|
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