Open AccessBreast Cancer Cells Transition from Mesenchymal to Amoeboid Migration in Tunable Three-Dimensional Silk–Collagen Hydrogels
Author(s) -
Amanda Khoo,
Thomas Valentin,
Susan E. Leggett,
Dhananjay Bhaskar,
Elisa M Bye,
Shoham Benmelech,
Blanche C. Ip,
Ian Y. Wong
Publication year - 2019
Publication title -
acs biomaterials science and engineering
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.082
H-Index - 50
ISSN - 2373-9878
DOI - 10.1021/acsbiomaterials.9b00519
Subject(s) - fibroin , extracellular matrix , self healing hydrogels , mesenchymal stem cell , silk , materials science , matrix (chemical analysis) , cell migration , microbiology and biotechnology , biomaterial , cell adhesion , cancer cell , biophysics , adhesion , cell , chemistry , nanotechnology , biology , cancer , composite material , biochemistry , polymer chemistry , genetics
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.