Glioblastoma Spheroid Invasion through Soft, Brain‐Like Matrices Depends on Hyaluronic Acid–CD44 Interactions

Abstract

Increased secretion of hyaluronic acid (HA), a glycosaminoglycan abundant in the brain extracellular matrix (ECM), correlates with worse clinical outcomes for glioblastoma (GBM) patients. GBM cells aggressively invade the brain parenchyma while encountering spatiotemporal changes in their local ECM, including HA concentration. To investigate how varying HA concentrations affect GBM invasion, patient‐derived GBM cells are cultured within a soft, 3D matrix in which HA concentration is precisely varied and cell migration observed. Data demonstrate that HA concentration can determine the invasive activity of patient‐derived GBM cells in a biphasic and highly sensitive manner, where the absolute concentration of HA at which cell migration peaked is specific to each patient‐derived line. Furthermore, evidence that this response relies on phosphorylated ezrin, which interacts with the intracellular domain of HA‐engaged CD44 to effectively link the actin cytoskeleton to the local ECM is provided. Overall, this study highlights CD44–HA binding as a major mediator of GBM cell migration that acts independently of integrins and focal adhesion complexes and suggests that targeting HA–CD44–ezrin interactions represents a promising therapeutic strategy to prevent tumor cell invasion in the brain.

Microenvironmental stiffness induces metabolic reprogramming in glioblastoma

“…Fabrication of 3D hydrogel matrices is described in detail in our previous work 18 , 20 and in STAR Methods . HA hydrogels were fabricated with a wide range of mechanical properties ( Figure S1A ), specifically to mimic the μ-compressive modulus of either tumor core (stiff hydrogels, E = 3,772 ± 1,471 Pa) or peritumoral (soft hydrogels, E = 339 ± 87 Pa) ECM ( Figure S1B , p < 0.0001).…”

“… 19 Furthermore, we found that invasion of GBM cells through 3D matrices only occurred in these softer, peritumoral-like matrices and required engagement of both CD44 and integrins. 19 , 20 …”

TS‐2021, a third‐generation oncolytic adenovirus that carried Ki67 promoter, TGF‐β2 5′UTR, and IL−15 against experimental glioblastoma

“…Furthermore, it also consists of MAPKs JNK and p38, mTOR, and PI3K signaling pathways 7,8 . Although the standard treatment for GBM has relied on maximum safety resection followed by adjuvant radiation and chemotherapy, most patients inevitably experience recurrence near the site of primary tumor resection with rare occurrences of extra‐neural metastases 9,10 . Therefore, this inimitable nature of glioma necessitates the development of more effective treatments to improve the prognosis of patients with GBM.…”

Microenvironmental Stiffness Induces Metabolic Reprogramming in Glioblastoma

“…19 Furthermore, we found that invasion of GBM cells through 3D matrices only occurred in these softer, peritumoral-like matrices and required engagement of both CD44 and integrins. 19,20 In the current study, we measured the regional differences in the compressive modulus of the tumor core, tumor edge, and peritumoral ECM tissue in patient-derived GBM tumors orthotopically implanted in mice. We then fabricated ECM-derived matrices with moduli matching these measurements for either tumor core or peritumoral tissue and used these matrices as 3D culture microenvironments for patient-derived GBM cells.…”