| Autor: |
Khoo AS; School of Engineering, Center for Biomedical Engineering. Brown University. 184 Hope St Box D, Providence, RI 02912, USA., Valentin TM; School of Engineering, Center for Biomedical Engineering. Brown University. 184 Hope St Box D, Providence, RI 02912, USA.; Current Address: Department of Health Sciences and Technology, ETH Zürich. Zürich, Switzerland., Leggett SE; School of Engineering, Center for Biomedical Engineering. Brown University. 184 Hope St Box D, Providence, RI 02912, USA.; Pathobiology Graduate Program. Brown University, Providence, RI, USA.; Current Address: Department of Chemical and Biological Engineering, Princeton University. Princeton, NJ 08544, USA., Bhaskar D; School of Engineering, Center for Biomedical Engineering. Brown University. 184 Hope St Box D, Providence, RI 02912, USA., Bye EM; School of Engineering, Center for Biomedical Engineering. Brown University. 184 Hope St Box D, Providence, RI 02912, USA., Benmelech S; School of Engineering, Center for Biomedical Engineering. Brown University. 184 Hope St Box D, Providence, RI 02912, USA., Ip BC; Pathobiology Graduate Program. Brown University, Providence, RI, USA., Wong IY; School of Engineering, Center for Biomedical Engineering. Brown University. 184 Hope St Box D, Providence, RI 02912, USA.; Pathobiology Graduate Program. Brown University, Providence, RI, USA. |
| Abstrakt: |
Invading cancer cells adapt their migration phenotype in response to mechanical and biochemical cues from the extracellular matrix. For instance, mesenchymal migration is associated with strong cell-matrix adhesions and an elongated morphology, while amoeboid migration is associated with minimal cell-matrix adhesions and a rounded morphology. However, it remains challenging to elucidate the role of matrix mechan-ics and biochemistry, since these are both dependent on ECM protein concentration. Here, we demonstrate a composite silk fibroin and collagen I hydrogel where stiffness and microstructure can be systematically tuned over a wide range. Using an overlay assay geometry, we show that the invasion of metastatic breast cancer cells exhibits a biphasic dependence on silk fibroin concentration at fixed collagen I concentration, first increasing as the hydrogel stiffness increases, then decreasing as the pore size of silk fibroin decreases. Indeed, mesenchymal morphology exhibits a similar biphasic depen-dence on silk fibroin concentration, while amoeboid morphologies were favored when cell-matrix adhesions were less effective. We used exogenous biochemical treatment to perturb cells towards increased contractility and a mesenchymal morphology, as well as to disrupt cytoskeletal function and promote an amoeboid morphology. Overall, we envision that this tunable biomaterial platform in a 96-well plate format will be widely applicable to screen cancer cell migration against combinations of designer biomaterials and targeted inhibitors. |
