Programmable dual-gel tumor-mimetic 3D culture platforms for studying effects of interstitial flow and transport coupling on cancer cell migration
Metastasis is responsible for the vast majority of cancer deaths. As the first step of metastasis, migration of tumor cells through the extracellular matrix (ECM) to the surrounding tissue is regulated by a variety of biochemical and biophysical signals in the ECM, which may even couple with each other to impose a combined effect. For example, interstitial flow—the slow convection of fluid occurring in the interstitial space of ECM—not only conjoins matrix permeability (or specific hydraulic conductivity) to provide direct mechanical cues to the resident cells through shear and normal stress, but also couples with biomolecular diffusion to induce chemotactic signals (e.g. CCR7-mediated autologous chemotaxis). Therefore, a mechanistic and quantitative understanding of the dependence of cancer cell migration on interstitial flow would require an ability to manipulate interstitial flow, matrix permeability, and bioactive molecules in the ECM without affecting other contributing factors such as stiffness and physical confinement.
However, this independent control remains a daunting task in traditional hydrogel-based culture models due to the inevitable correlation among various properties of a hydrogel and the lack of means of manipulating bioactive molecules in the culture matrix. To address this research gap, we develop tumor-mimetic, dual-gel 3D cell culture models that enable an independent control of the key matrix properties and the bioactive molecules therein. In addition, with the new microfluidic culture platforms, we aim at quantitating interstitial flow-induced CCR7-dependent autologous chemotaxis and integrin-mediated FAK activation in breast cancer cells and identifying signaling mechanisms for the varied migration of breast cancer cells due to cancer associated fibroblasts.
Collaborators: Sihong Wang at CCNY; Xuejun Jiang at Sloan Kettering Institute; Nancy Du at Weill Cornell Medicine