Glioblastoma is the most common and deadly malignant brain cancer. We now demonstrate that loss of function of the endosomal GTPase Rab35 in human brain tumor initiating cells (BTICs) increases glioblastoma growth and decreases animal survival following BTIC implantation in mouse brains. Mechanistically, we identify that the GTPase Arf5 interacts with the guanine nucleotide exchange factor (GEF) for Rab35, DENND1/connecdenn, and allosterically enhances its GEF activity toward Rab35. Knockdown of either Rab35 or Arf5 increases cell migration, invasiveness, and self-renewal in culture and enhances the growth and invasiveness of BTIC-initiated brain tumors in mice. RNAseq of the tumors reveals up-regulation of the tumor-promoting transcription factor SPOCD1, and disruption of the Arf5/Rab35 axis in glioblastoma cells leads to strong activation of the epidermal growth factor receptor, with resulting enhancement of SPOCD1 levels. These discoveries reveal an unexpected cascade between an Arf and a Rab and indicate a role for the cascade, and thus endosomal trafficking, in brain tumors.
Skip Nav Destination
Article navigation
1 February 2021
Article|
January 14 2021
An Arf/Rab cascade controls the growth and invasiveness of glioblastoma
Gopinath Kulasekaran
,
Gopinath Kulasekaran
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Search for other works by this author on:
Mathilde Chaineau
,
Mathilde Chaineau
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Search for other works by this author on:
Valerio Emilio Crescenzo Piscopo
,
Valerio Emilio Crescenzo Piscopo
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Search for other works by this author on:
Federica Verginelli
,
Federica Verginelli
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Search for other works by this author on:
Maryam Fotouhi
,
Maryam Fotouhi
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Search for other works by this author on:
Martine Girard
,
Martine Girard
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Search for other works by this author on:
Yeman Tang
,
Yeman Tang
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Search for other works by this author on:
Rola Dali
,
Rola Dali
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Search for other works by this author on:
Rita Lo
,
Rita Lo
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Search for other works by this author on:
Stefano Stifani
,
Stefano Stifani
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Search for other works by this author on:
Peter S. McPherson
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Correspondence to Peter S. McPherson: peter.mcpherson@mcgill.ca
Search for other works by this author on:
Gopinath Kulasekaran
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Mathilde Chaineau
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Valerio Emilio Crescenzo Piscopo
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Federica Verginelli
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Maryam Fotouhi
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Martine Girard
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Yeman Tang
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Rola Dali
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Rita Lo
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Stefano Stifani
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Peter S. McPherson
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Correspondence to Peter S. McPherson: peter.mcpherson@mcgill.ca
Received:
April 29 2020
Revision Received:
October 27 2020
Accepted:
November 23 2020
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding:
Royal Society of Canada
(NO AWARD)
© 2021 Kulasekaran et al.
2021
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2021) 220 (2): e202004229.
Article history
Received:
April 29 2020
Revision Received:
October 27 2020
Accepted:
November 23 2020
Citation
Gopinath Kulasekaran, Mathilde Chaineau, Valerio Emilio Crescenzo Piscopo, Federica Verginelli, Maryam Fotouhi, Martine Girard, Yeman Tang, Rola Dali, Rita Lo, Stefano Stifani, Peter S. McPherson; An Arf/Rab cascade controls the growth and invasiveness of glioblastoma. J Cell Biol 1 February 2021; 220 (2): e202004229. doi: https://doi.org/10.1083/jcb.202004229
Download citation file:
Sign in
Don't already have an account? Register
Client Account
You could not be signed in. Please check your email address / username and password and try again.
Sign in via your Institution
Sign in via your Institution
2,039
Views
0
Citations
Advertisement
Advertisement