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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.