Handling Editor: Andrew Ewald
ABSTRACT
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.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: A.J.E., F.F.; Methodology: A.B., A.J.E., F.F.; Software: A.B.; Validation: A.B.; Formal analysis: A.B., P.B., A.D.P., B.Y., J.K.P.; Investigation: A.B., M.E., P.B., A.D.P., B.Y., J.K.P.; Resources: A.J.E., F.F.; Writing - original draft: A.B., A.J.E., F.F.; Writing - review & editing: A.B., A.J.E., F.F.; Supervision: A.J.E., F.F.; Project administration: A.J.E., F.F.; Funding acquisition: A.J.E., F.F.
Funding
Funding was provided by direct support from the Ludwig Institute for Cancer Research, National Institutes of Health (grant numbers: R01CA206880 and R21CA217735 to A.J.E., R01NS080939 to F.F., and R01NS116802 to A.J.E. and F.F.), the National Science Foundation (grant number: CMMI-1763139 to A.J.E.) and the National Science Foundation Graduate Research Fellowship program (to A.B.). Deposited in PMC for release after 12 months.
Supplementary information
Supplementary information available online at https://jcs.biologists.org/lookup/doi/10.1242/jcs.247189.supplemental
- Received April 3, 2020.
- Accepted November 9, 2020.
- © 2020. Published by The Company of Biologists Ltd
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