A mode of cell adhesion and migration facilitated by CD44-dependent microtentacles

Abstract

<jats:p>The structure and mechanics of many connective tissues are dictated by a collagen-rich extracellular matrix (ECM), where collagen fibers provide topological cues that direct cell migration. However, comparatively little is known about how cells navigate the hyaluronic acid (HA)-rich, nanoporous ECM of the brain, a problem with fundamental implications for development, inflammation, and tumor invasion. Here, we demonstrate that glioblastoma cells adhere to and invade HA-rich matrix using microtentacles (McTNs), which extend tens of micrometers from the cell body and are distinct from filopodia. We observe these structures in continuous culture models and primary patient-derived tumor cells, as well as in synthetic HA matrix and organotypic brain slices. High-magnification and superresolution imaging reveals McTNs are dynamic, CD44-coated tubular protrusions containing microtubules and actin filaments, which respectively drive McTN extension and retraction. Molecular mechanistic studies reveal that McTNs are stabilized by an interplay between microtubule-driven protrusion, actomyosin-driven retraction, and CD44-mediated adhesion, where adhesive and cytoskeletal components are mechanistically coupled by an IQGAP1–CLIP170 complex. McTNs represent a previously unappreciated mechanism through which cells engage nanoporous HA matrix and may represent an important molecular target in physiology and disease.</jats:p>

The Density and Length of Filopodia Associate with the Activity of Hyaluronan Synthesis in Tumor Cells

“…Interestingly, CD44 regulates functional and structural plasticity of dendritic spines, specific protrusions that develop from dendritic filopodia [ 40 ]. Furthermore, in a recent report, CD44 was reported to be crucial for microtentacles, specific protrusions formed by glioblastoma cells in hyaluronan-rich extracellular matrix (ECM) [ 41 ]. Our results confirm that CD44 is not essential for the formation of filopodia in MKN74 cells.…”

Terminal Schwann Cell Aging: Implications for Age-Associated Neuromuscular Dysfunction

“…CD44 is a cell surface glycoprotein which regulates cell-cell and cell-matrix interactions in several tissues [ 140 , 141 ]. It is involved in cell migration [ 142 , 143 ], it is able to promote cell invasion into a hyaluronan-rich matrix [ 144 ] and promotes the formation of microtentacles to facilitate migration [ 145 ].…”

“…In Schwann cells of developing peripheral nerves, CD44 constitutively associates with ErbB2 and ErbB3, where it is required for receptor heterodimerization [147]. Since both CD44 and ErbB are important regulators of morphological plasticity and cell migration [142][143][144][145][149][150][151][152], the NRG-ErbB-CD44 axis may be involved in the regulation of tSC morphological plasticity, migration and phenotypic stability during adulthood and aging.…”

Practical Review on Preclinical Human 3D Glioblastoma Models: Advances and Challenges for Clinical Translation

“…Slice cultures conserve the presence of vessels [ 87 ], microglial cells [ 84 , 90 ] and astrocytes [ 82 ]. Furthermore, thin structures can also be observed such as microtentacles and filopodia [ 91 ].…”

“…Slice cultures conserve the presence of vessels [87], microglial cells [84,90] and astrocytes [82]. Furthermore, thin structures can also be observed such as microtentacles and filopodia [91]. Organotypic cultures allow the manipulation of both tumor cells and the brain microenvironment by treating the slice with small molecule inhibitors or by using different genetically engineered mouse models as donors, providing a diversity of applications.…”