Engineering subarachnoid trabeculae with electrospun poly(caprolactone) (PCL) scaffolds to study leptomeningeal metastasis in medulloblastoma.

ABSTRACT

Leptomeningeal metastasis (LM) occurs when cancer cells infiltrate the subarachnoid space (SAS) and metastasize to the fibrous structures that surround the brain and spinal cord. These structures include the leptomeninges (i.e., the pia mater and arachnoid mater), as well as subarachnoid trabeculae, which are collagen-rich fibers that provide mechanical structure for the SAS, support resident cells, and mediate flow of cerebrospinal fluid (CSF). Although there is a strong expectation that the presence of fibers within the SAS influences LM to be a major driver of tumor progression and lethality, exactly how trabecular architecture relates to the process of metastasis in cancer is poorly understood. This lack of understanding is likely due in part to the difficulty of accessing and manipulating this tissue compartment in vivo. Here, we utilized electrospun polycaprolactone (PCL) to produce structures bearing remarkable morphological similarity to native SAS fiber architecture. First, we profiled the native architecture of leptomeningeal and trabecular fibers collected from rhesus macaque monkeys, evaluating both qualitative and quantitative differences in fiber ultrastructure for various regions of the CNS. We then varied electrospinning parameters to produce a small library of PCL scaffolds possessing distinct architectures mimicking the range of fiber properties observed in vivo. For proof of concept, we studied the metastasis-related behaviors of human pediatric medulloblastoma cells cultured in different fiber microenvironments. These studies demonstrated that a more open, porous fiber structure facilitates DAOY cell spread across and infiltration into the meningeal mimic. Our results present a new tissue engineered model of the subarachnoid space and affirm the expectation that fiber architecture plays an important role in mediating metastasis-related behaviors in an in vitro model of pediatric medulloblastoma.