Extracellular matrix rigidity modulates neuroblastoma cell differentiation and N-myc expression

Inducing tumor cells to differentiate is an important therapeutic goal in cancer, especially in neuroblastoma, one of the few malignancies that demonstrates spontaneous differentiation and regression to a benign state [1]. Previous research has shown that cross-talk between neuroblastoma cells and the extracellular matrix (ECM) influences differentiation [2], and recent studies have identified key genes that regulate those interactions [3,4]. Neuroblastoma differentiation can also be induced pharmacologically with retinoic acid (RA) [5]; indeed, RA has been demonstrated to have significant clinical benefit in neuroblastoma, which has resulted in inclusion of RA in treatment regimens for high risk disease [6-8]. RA-induced signaling in neuroblastoma affects expression of N-Myc and other proto-oncogenes but also has been shown to alter the expression and activity of integrins, Rho GTPases, and the actin cytoskeleton. These molecular components act in concert to sense and process signals from the ECM [9-12] and to mediate cell shape and cytoarchitecture. In addition, altering the biochemical composition of the ECM itself induces morphological differentiation of neuroblastoma cells [13-15]. Together, these data strongly hint that signals encoded in the ECM may play a significant role in guiding NB differentiation.While the ECM is classically regarded to instruct cell behavior primarily through biochemical recognition by cell adhesion receptors, it has become increasingly clear that another component of ECM-based signaling is fundamentally biophysical in nature. In particular, the mechanical rigidity (stiffness) of the ECM can profoundly alter cellular behavior, including morphology, motility, and proliferation [16-18]. While the mechanisms of this "rigidity sensing" remain incompletely understood, ECM rigidity appears to dictate the amount of stress or strain the cellular cytoskeleton can impose upon adhesion plaques, which is then sensed by specific mechanosensory mole