Cancer cell migration in collagen-hyaluronan composite extracellular matrices
Hyaluronan (HA) is a key component in the tumor microenvironment (TME) that participates in cancer growth and invasiveness. While the molecular weight (MW) dependent properties of HA can cause tumor-promoting and -repressing effects, the elevated levels of HA in the TME impedes drug delivery. The degradation of HA using hyaluronidases (HYALs), resulting in fragments of HA, is a way to overcome this, but the consequences of changes in HA molecular weight and concentration is currently unknown. Therefore, it is critical to understand the MW-dependent biological effects of HA. Here we examine the influence of HA molecular weight on biophysical properties that regulate cell migration and extracellular matrix (ECM) remodeling. In our study, we used vLMW, LMW and HMW HA at different physiologically relevant concentrations, with a particular interest in correlating the mechanical and structural properties to different cell functions. The elastic modulus, collagen network pore size and collagen fiber diameter increased with increasing HA concentration. Although the collagen network pore size increased, these pores were filled with the bulky HA molecules. Consequently, cell migration decreased with increase in HA concentration due to multiple, long-lived and unproductive protrusions, suggesting the influence of steric factors. Surprisingly, even though elastic modulus increased with HA molecular weight and concentration, gel compaction assays showed an increased degree of ECM compaction among HMW HA gels at high concentrations (2 and 4 mg mL−1 [0.2 and 0.4%]). These results were not seen in collagen gels that lacked HA, but had similar stiffness. HA appears to have the effect of decreasing migration and increasing collagen network contraction, but only at high HA molecular weight. Consequently, changes in HA molecular weight can have relatively large effects on cancer cell behavior.
This is a manuscript of an article published as Veettil, Shalini R. Unnikandam, Dohgyu Hwang, Jacinta Correia, Michael D. Bartlett, and Ian C. Schneider. "Cancer Cell Migration in Collagen-hyaluronan Composite Extracellular Matrices." Acta Biomaterialia (2021). DOI: 10.1016/j.actbio.2021.06.009. Published with permission.