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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-SRLB-9)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
United States
Zip Code
Chen, Mo; Peters, Alec; Huang, Tao et al. (2016) Ras Dimer Formation as a New Signaling Mechanism and Potential Cancer Therapeutic Target. Mini Rev Med Chem 16:391-403
Laklai, Hanane; Miroshnikova, Yekaterina A; Pickup, Michael W et al. (2016) Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat Med 22:497-505
Gao, Sizhi P; Chang, Qing; Mao, Ninghui et al. (2016) JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors. Sci Signal 9:ra33
Ou, Guanqing; Thakar, Dhruv; Tung, Jason C et al. (2016) Visualizing mechanical modulation of nanoscale organization of cell-matrix adhesions. Integr Biol (Camb) 8:795-804
Northcott, Josette M; Northey, Jason J; Barnes, J Matthew et al. (2015) Fighting the force: Potential of homeobox genes for tumor microenvironment regulation. Biochim Biophys Acta 1855:248-53
Nickerson, Andrew; Huang, Tao; Lin, Li-Jung et al. (2015) Photoactivated Localization Microscopy with Bimolecular Fluorescence Complementation (BiFC-PALM). J Vis Exp :e53154
Chang, Ching-Wei; Kumar, Sanjay (2015) Differential Contributions of Nonmuscle Myosin II Isoforms and Functional Domains to Stress Fiber Mechanics. Sci Rep 5:13736
Lee, Somin Eunice; Chen, Qian; Bhat, Ramray et al. (2015) Reversible Aptamer-Au Plasmon Rulers for Secreted Single Molecules. Nano Lett 15:4564-70
Tung, Jason C; Barnes, J Matthew; Desai, Shraddha R et al. (2015) Tumor mechanics and metabolic dysfunction. Free Radic Biol Med 79:269-80
Diamond, Marc I; Cai, Shirong; Boudreau, Aaron et al. (2015) Subcellular localization and Ser-137 phosphorylation regulate tumor-suppressive activity of profilin-1. J Biol Chem 290:9075-86

Showing the most recent 10 out of 124 publications