Sprouty2 Drives Drug Resistance and Proliferation in Glioblastoma.
Glioblastoma multiforme (GBM) is notoriously resistant to therapy, and the development of a durable cure will require the identification of broadly relevant regulators of GBM cell tumorigenicity and survival. Here, we identify Sprouty2 (SPRY2), a known regulator of receptor tyrosine kinases (RTK), as one such regulator. SPRY2 knockdown reduced proliferation and anchorage-independent growth in GBM cells and slowed xenograft tumor growth in mice. SPRY2 knockdown also promoted cell death in response to coinhibition of the epidermal growth factor receptor (EGFR) and the c-MET receptor in GBM cells, an effect that involved regulation of the ability of the p38 mitogen-activated protein kinase (MAPK) to drive cell death in response to inhibitors. Analysis of data from clinical tumor specimens further demonstrated that SPRY2 protein is definitively expressed in GBM tissue, that SPRY2 expression is elevated in GBM tumors expressing EGFR variant III (EGFRvIII), and that elevated SPRY2 mRNA expression portends reduced GBM patient survival. Overall, these results identify SPRY2 and the pathways it regulates as novel candidate biomarkers and therapeutic targets in GBM.


CONCLUSIONS
SPRY2, counter to its roles in other cancer settings, promotes glioma cell and tumor growth and cellular resistance to targeted inhibitors of oncogenic RTKs, thus making SPRY2 and the cell signaling processes it regulates potential novel therapeutic targets in glioma.
Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania.
Alice M
AM
Walsh
Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania.
Gurpreet S
GS
Kapoor
Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania.
Janine M
JM
Buonato
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania. Howared Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
Lijoy K
LK
Mathew
Center for Systems and Computational Biology, Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Yingtao
Y
Bi
Center for Systems and Computational Biology, Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Ramana V
RV
Davuluri
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Maria
M
Martinez-Lage
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania. Howared Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
M Celeste
MC
Simon
Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Donald M
DM
O'Rourke
Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania. mlazzara@seas.upenn.edu.
Matthew J
MJ
Lazzara
D000328:Adult; D000818:Animals; D014408:Biomarkers, Tumor; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D054637:Dual-Specificity Phosphatases / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000378:metabolism; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000378:metabolism
D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; C485561:SPRY2 protein, human; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse; C120407:DUSP10 protein, human; C505617:Dusp10 protein, mouse; D054639:Mitogen-Activated Protein Kinase Phosphatases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D054637:Dual-Specificity Phosphatases; C517020:Dusp1 protein, mouse