Kinome-wide shRNA screen identifies the receptor tyrosine kinase AXL as a key regulator for mesenchymal glioblastoma stem-like cells.
Glioblastoma is a highly lethal cancer for which novel therapeutics are urgently needed. Two distinct subtypes of glioblastoma stem-like cells (GSCs) were recently identified: mesenchymal (MES) and proneural (PN). To identify mechanisms to target the more aggressive MES GSCs, we combined transcriptomic expression analysis and kinome-wide short hairpin RNA screening of MES and PN GSCs. In comparison to PN GSCs, we found significant upregulation and phosphorylation of the receptor tyrosine kinase AXL in MES GSCs. Knockdown of AXL significantly decreased MES GSC self-renewal capacity in vitro and inhibited the growth of glioblastoma patient-derived xenografts. Moreover, inhibition of AXL with shRNA or pharmacologic inhibitors also increased cell death significantly more in MES GSCs. Clinically, AXL expression was elevated in the MES GBM subtype and significantly correlated with poor prognosis in multiple cancers. In conclusion, we identified AXL as a potential molecular target for novel approaches to treat glioblastoma and other solid cancers.
Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA; Department of Neurosurgery, The First Hospital, China Medical University, Shenyang, Liaoning 110001, China.
Peng
P
Cheng
Division of Molecular Genetics, German Cancer Research Center, Heidelberg 69120, Germany.
Emma
E
Phillips
Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA.
Sung-Hak
SH
Kim
Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA.
David
D
Taylor
Division of Biostatistics, German Cancer Research Center, Heidelberg 69120, Germany.
Thomas
T
Hielscher
Division of Molecular Genetics, German Cancer Research Center, Heidelberg 69120, Germany.
Laura
L
Puccio
Department of Cell, Developmental, and Integrative Biology (CDIB), University of Alabama, Birmingham, AL 35294, USA.
Anita B
AB
Hjelmeland
Division of Molecular Genetics, German Cancer Research Center, Heidelberg 69120, Germany.
Peter
P
Lichter
Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA; James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. Electronic address: ichiro.nakano@osumc.edu.
Ichiro
I
Nakano
Division of Molecular Genetics, German Cancer Research Center, Heidelberg 69120, Germany. Electronic address: v.goidts@dkfz.de.
Violaine
V
Goidts
D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology; D063646:Carcinogenesis; D049109:Cell Proliferation; D005909:Glioblastoma / Q000235:genetics / Q000401:mortality / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D000094963:Axl Receptor Tyrosine Kinase
D018960:Hyaluronan Receptors; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase