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Mechanobiology of Disease
Poster Abstracts
98
80-POS
Board 80
Nanoscale Extracellular Matrix Properties Influence Chemoresistance
Jennifer L. Young
, Sascha Klar, Joachim P. Spatz.
Max Planck Institute for Medical Research, Stuttgart, Germany.
Cancer cell-ECM interactions have been shown to positively influence cancer cell survival and
invasion by conferring adhesion-based resistance in response to chemotherapeutic drugs and
subsequently upregulating pathways driving metastasis. The frequent inability of chemotherapy
to provide a long-term, complete cure may be attributed to this specific, adhesion-mediated
resistance of malignant cells to chemotherapeutic interventions. Here, we present a platform
designed to identify and perturb protective matrix properties on the nanoscale in a high-
throughput manner, allowing for the conversion of chemoresistant cells into chemosensitive
ones, and subsequently examining these nanoscale properties in combination with mechanical
properties of the ECM. Block copolymer micelle nanolithography (BCML) was utilized to create
large, scalable arrays of defined ligand presentation at 50 and 75 nm spacing. Breast cancer cell
lines were then treated with chemotherapeutic drugs in order to identify the most protective
ligand interactions, as determined by cell survival assays and immunofluorescence.
Chemoresistance was found to greatly depend on ligand presentation, e.g. laminin is protective at
75 nm spacing but not 50 nm. By utilizing BCML in conjunction with soft polymer transfer
nanolithography, the influence of mechanical matrix properties in parallel with ligand
presentation was analyzed on 2D substrates and inside 3D microchannels of 125 µm diameter. In
both 2D and 3D systems, tumorigenic stiffness hydrogels (5 kPa) were more effective than
softer, healthy breast tissue hydrogels (1 kPa) in upregulating cell area, polarity and motility,
which have all been hypothesized to play a role in chemoresistance. Additionally, mechanical
properties were shown to influence chemosurvival in conjunction with ligand type and spacing,
e.g. survival on laminin was enhanced on 1 kPa vs. 5 kPa hydrogels for 50 nm spacing but not 75
nm. These scalable platforms allow for screening several aspects of ECM-conferred
chemoresistance in a highly defined manner.