Journal
JOURNAL OF CELL SCIENCE
Volume 133, Issue 24, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.247189
Keywords
Cancer; Extracellular matrix; Adhesion; Invasion
Categories
Funding
- Ludwig Institute for Cancer Research, National Institutes of Health [R01CA206880, R21CA217735, R01NS080939, R01NS116802]
- National Science Foundation [CMMI-1763139]
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A lack of biological markers has limited our ability to identify the invasive cells responsible for glioblastoma multiforme (GBM). To become migratory and invasive, cells must downregulate matrix adhesions, which could be a physical marker of invasive potential. We engineered murine astrocytes with common GBM mutations, e.g. Ink4a (Ink) or PTEN deletion and expressing a constitutively active EGF receptor truncation (EGFRvIII), to elucidate their effect on adhesion. While loss of Ink or PTEN did not affect adhesion, counterparts expressing EGFRvIII were significantly less adhesive. EGFRvIII reduced focal adhesion size and number, and these cells - with more labile adhesions - displayed enhanced migration. Regulation appears to depend not on physical receptor association to integrins but, rather, on the activity of the receptor kinase, resulting in transcriptional integrin repression. Interestingly, EGFRvIII intrinsic signals can be propagated by cytokine crosstalk to cells expressing wild-type EGFR, resulting in reduced adhesion and enhanced migration. These data identify potential intrinsic and extrinsic mechanisms that gliomas use to invade surrounding parenchyma.
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