Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
J Cell Biol. 2021 Feb 1;220(2). doi: 10.1083/jcb.202004229.
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.
胶质母细胞瘤是最常见和最致命的恶性脑癌。我们现在证明，在人类脑肿瘤起始细胞（BTICs）中丧失内体 GTP 酶 Rab35 的功能会增加胶质母细胞瘤的生长，并减少 BTIC 植入小鼠大脑后动物的存活率。在机制上，我们确定 GTP 酶 Arf5 与 Rab35 的鸟嘌呤核苷酸交换因子（GEF）DENND1/connecdenn 相互作用，并别构增强其对 Rab35 的 GEF 活性。Rab35 或 Arf5 的敲低均增加了细胞在培养中的迁移、侵袭和自我更新能力，并增强了 BTIC 起始的脑肿瘤在小鼠中的生长和侵袭。肿瘤的 RNAseq 揭示了促肿瘤转录因子 SPOCD1 的上调，并且在胶质母细胞瘤细胞中破坏 Arf5/Rab35 轴会导致表皮生长因子受体的强烈激活，从而增强 SPOCD1 水平。这些发现揭示了 Arf 和 Rab 之间的一个意想不到的级联反应，并表明该级联反应（以及因此内体运输）在脑肿瘤中起作用。
