Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 21, Pages 11432-11443Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1914294117
Keywords
glioblastoma; hyaluronic acid; extracellular matrix; mechanobiology; motility
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Funding
- NIH S10 program [1S10OD018136-01]
- NIH [F31CA228317, F31GM119329, R21CA174573, R21EB016359, R01CA227136, R01GM122375]
- European Union's Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie Grant [752097]
- W. M. Keck Foundation
- NSF [CHE-1554717]
- Marie Curie Actions (MSCA) [752097] Funding Source: Marie Curie Actions (MSCA)
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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 super-resolution 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 thatMcTNs are stabilized by an interplay between microtubuledriven 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.
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