Targeting glioblastoma tumor hyaluronan to enhance therapeutic interventions that regulate metabolic cell properties.

Despite extensive advances in cancer research, glioblastoma (GBM) still remains a very locally invasive and thus challenging tumor to treat, with a poor median survival. Tumor cells remodel their microenvironment and utilize extracellular matrix to promote invasion and therapeutic resistance. We aim here to determine how GBM cells exploit hyaluronan (HA) to maintain proliferation using ligand-receptor dependent and ligand-receptor independent signaling. We use tissue engineering approaches to recreate the three-dimensional tumor microenvironment in vitro, then analyze shifts in metabolism, hyaluronan secretion, HA molecular weight distribution, as well as hyaluronan synthetic enzymes (HAS) and hyaluronidases (HYAL) activity in an array of patient derived xenograft GBM cells. We reveal that endogenous HA plays a role in mitochondrial respiration and cell proliferation in a tumor subtype dependent manner. We propose a tumor specific combination treatment of HYAL and HAS inhibitors to disrupt the HA stabilizing role in GBM cells. Taken together, these data shed light on the dual metabolic and ligand - dependent signaling roles of hyaluronan in glioblastoma. Significance: The control of aberrant hyaluronan metabolism in the tumor microenvironment can improve the efficacy of current treatments. Bioengineered preclinical models demonstrate potential to predict, stratify and accelerate the development of cancer treatments.

Microphysiological systems to study tumor-stroma interactions in brain cancer.

Brain tumors still lack effective treatments, and the mechanisms of tumor progression and therapeutic resistance are unclear. Multiple parameters affect cancer prognosis (e.g., type and grade, age, location, size, and genetic mutations) and election of suitable treatments is based on preclinical models and clinical data. However, most candidate drugs fail in human trials due to inefficacy. Cell lines and tissue culture plates do not provide physiologically relevant environments, and animal models are not able to adequately mimic characteristics of disease in humans. Therefore, increasing technological advances are focusing on in vitro and computational modeling to increase the throughput and predicting capabilities of preclinical systems. The extensive use of these therapeutic agents requires a more profound understanding of the tumor-stroma interactions, including neural tissue, extracellular matrix, blood-brain barrier, astrocytes and microglia. Microphysiological brain tumor models offer physiologically relevant vascularized 'minitumors' that can help deciphering disease mechanisms, accelerating the drug discovery and predicting patient's response to anticancer treatments. This article reviews progress in tumor-on-a-chip platforms that are designed to comprehend the particular roles of stromal cells in the brain tumor microenvironment.