RT Journal Article SR Electronic T1 An Arf/Rab cascade controls the growth and invasiveness of glioblastoma JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.04.30.070334 DO 10.1101/2020.04.30.070334 A1 Gopinath Kulasekaran A1 Mathilde Chaineau A1 Valerio E. Piscopo A1 Federica Verginelli A1 Maryam Fotouhi A1 Martine Girard A1 Yeman Tang A1 Rola Dali A1 Rita Lo A1 Stefano Stifani A1 Peter S. McPherson YR 2020 UL http://biorxiv.org/content/early/2020/11/16/2020.04.30.070334.abstract AB 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 brain. 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 towards 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 upregulation 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.Competing Interest StatementThe authors have declared no competing interest.