title: A leak pathway for luminal protons in endosomes drives oncogenic signalling in glioblastoma.
abstract: Epidermal growth factor receptor (EGFR) signalling is a potent driver of glioblastoma, a malignant and lethal form of brain cancer. Disappointingly, inhibitors targeting receptor tyrosine kinase activity are not clinically effective and EGFR persists on the plasma membrane to maintain tumour growth and invasiveness. Here we show that endolysosomal pH is critical for receptor sorting and turnover. By functioning as a leak pathway for protons, the Na(+)/H(+) exchanger NHE9 limits luminal acidification to circumvent EGFR turnover and prolong downstream signalling pathways that drive tumour growth and migration. In glioblastoma, NHE9 expression is associated with stem/progenitor characteristics, radiochemoresistance, poor prognosis and invasive growth in vitro and in vivo. Silencing or inhibition of NHE9 in brain tumour-initiating cells attenuates tumoursphere formation and improves efficacy of EGFR inhibitor. Thus, NHE9 mediates inside-out control of oncogenic signalling and is a highly druggable target for pan-specific receptor clearance in cancer therapy.
authors: Department of Physiology, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
authors: Kalyan C
authors: KC
authors: Kondapalli
authors: Department of Physiology, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
authors: Jose P
authors: JP
authors: Llongueras
authors: Department of Neurosurgery, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
authors: Vivian
authors: V
authors: Capilla-González
authors: Department of Physiology, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
authors: Hari
authors: H
authors: Prasad
authors: Department of Physiology, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
authors: Anniesha
authors: A
authors: Hack
authors: Department of Neurosurgery, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
authors: Christopher
authors: C
authors: Smith
authors: Department of Neurosurgery, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
authors: Hugo
authors: H
authors: Guerrero-Cázares
authors: Department of Neurosurgery, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
authors: Alfredo
authors: A
authors: Quiñones-Hinojosa
authors: Department of Physiology, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
authors: Rajini
authors: R
authors: Rao
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D011992:Endosomes / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology; D011379:Prognosis; D011522:Protons; D011990:Receptors, Transferrin / Q000378:metabolism; D015398:Signal Transduction; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology
chemical_list: D011522:Protons; D011990:Receptors, Transferrin; C478541:SLC9A9 protein, human; D017923:Sodium-Hydrogen Exchangers; C512478:EGFR protein, human; D066246:ErbB Receptors