System-level analysis of neuroblastoma tumor-initiating cells implicates AURKB as a novel drug target for neuroblastoma.
OBJECTIVE
Neuroblastoma (NB) is an aggressive tumor of the developing peripheral nervous system that remains difficult to cure in the advanced stages. The poor prognosis for high-risk NB patients is associated with common disease recurrences that fail to respond to available therapies. NB tumor-initiating cells (TICs), isolated from metastases and primary tumors, may escape treatment and contribute to tumor relapse. New therapies that target the TICs may therefore prevent or treat tumor recurrences.


METHODS
We undertook a system-level characterization of NB TICs to identify potential drug targets against recurrent NB. We used next-generation RNA sequencing and/or human exon arrays to profile the transcriptomes of 11 NB TIC lines from six NB patients, revealing genes that are highly expressed in the TICs compared with normal neural crest-like cells and unrelated cancer tissues. We used gel-free two-dimensional liquid chromatography coupled to shotgun tandem mass spectrometry to confirm the presence of proteins corresponding to the most abundant TIC-enriched transcripts, thereby providing validation to the gene expression result.


RESULTS
Our study revealed that genes in the BRCA1 signaling pathway are frequently misexpressed in NB TICs and implicated Aurora B kinase as a potential drug target for NB therapy. Treatment with a selective AURKB inhibitor was cytotoxic to NB TICs but not to the normal neural crest-like cells.


CONCLUSIONS
This work provides the first high-resolution system-level analysis of the transcriptomes of 11 primary human NB TICs and identifies a set of candidate NB TIC-enriched transcripts for further development as therapeutic targets.
Morozova
Olena
O
Genome Sciences Centre, BC Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada. omorozova@bcgsc.ca
Vojvodic
Milijana
M
Grinshtein
Natalie
N
Hansford
Loen M
LM
Blakely
Kim M
KM
Maslova
Alexandra
A
Hirst
Martin
M
Cezard
Timothee
T
Morin
Ryan D
RD
Moore
Richard
R
Smith
Kristen M
KM
Miller
Freda
F
Taylor
Paul
P
Thiessen
Nina
N
Varhol
Richard
R
Zhao
Yongjun
Y
Jones
Steven
S
Moffat
Jason
J
Kislinger
Thomas
T
Moran
Michael F
MF
Kaplan
David R
DR
Marra
Marco A
MA
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D064107:Aurora Kinase B; D064127:Aurora Kinases; D002853:Chromatography, Liquid / Q000379:methods; D004353:Drug Evaluation, Preclinical; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D046228:Microarray Analysis; D058990:Molecular Targeted Therapy / Q000379:methods; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D049490:Systems Biology / Q000379:methods; D053719:Tandem Mass Spectrometry / Q000379:methods; D035703:Therapies, Investigational / Q000379:methods / Q000639:trends; D054928:Validation Studies as Topic
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases