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Publication : Myosin IIA suppresses glioblastoma development in a mechanically sensitive manner.

First Author  Picariello HS Year  2019
Journal  Proc Natl Acad Sci U S A Volume  116
Issue  31 Pages  15550-15559
PubMed ID  31235578 Mgi Jnum  J:278335
Mgi Id  MGI:6342670 Doi  10.1073/pnas.1902847116
Citation  Picariello HS, et al. (2019) Myosin IIA suppresses glioblastoma development in a mechanically sensitive manner. Proc Natl Acad Sci U S A 116(31):15550-15559
abstractText  The ability of glioblastoma to disperse through the brain contributes to its lethality, and blocking this behavior has been an appealing therapeutic approach. Although a number of proinvasive signaling pathways are active in glioblastoma, many are redundant, so targeting one can be overcome by activating another. However, these pathways converge on nonredundant components of the cytoskeleton, and we have shown that inhibiting one of these-the myosin II family of cytoskeletal motors-blocks glioblastoma invasion even with simultaneous activation of multiple upstream promigratory pathways. Myosin IIA and IIB are the most prevalent isoforms of myosin II in glioblastoma, and we now show that codeleting these myosins markedly impairs tumorigenesis and significantly prolongs survival in a rodent model of this disease. However, while targeting just myosin IIA also impairs tumor invasion, it surprisingly increases tumor proliferation in a manner that depends on environmental mechanics. On soft surfaces myosin IIA deletion enhances ERK1/2 activity, while on stiff surfaces it enhances the activity of NFkappaB, not only in glioblastoma but in triple-negative breast carcinoma and normal keratinocytes as well. We conclude myosin IIA suppresses tumorigenesis in at least two ways that are modulated by the mechanics of the tumor and its stroma. Our results also suggest that inhibiting tumor invasion can enhance tumor proliferation and that effective therapy requires targeting cellular components that drive both proliferation and invasion simultaneously.
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