Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor in pediatrics, with rare occurrences of primary and metastatic tumors in the central nervous system (CNS). We previously reported the overexpression of the polo-like kinase 4 (PLK4) in embryonal brain tumors. PLK4 has also been found to be overexpressed in a variety of peripheral adult tumors and recently in peripheral NB. Here, we investigated PLK4 expression in NBs of the CNS (CNS-NB) and validated our findings by performing a multi-platform transcriptomic meta-analysis using publicly available data. We evaluated the PLK4 expression by quantitative real-time PCR (qRT-PCR) on the CNS-NB samples and compared the relative expression levels among other embryonal and non-embryonal brain tumors. The relative PLK4 expression levels of the NB samples were found to be significantly higher than the non-embryonal brain tumors (p-value < 0.0001 in both our samples and in public databases). Here, we expand upon our previous work that detected PLK4 overexpression in pediatric embryonal tumors to include CNS-NB. As we previously reported, inhibiting PLK4 in embryonal tumors led to decreased tumor cell proliferation, survival, invasion and migration in vitro and tumor growth in vivo, and therefore PLK4 may be a potential new therapeutic approach to CNS-NB.
Highlights
Embryonal tumors of the central nervous system (CNS) are poorly differentiated tumors resembling the developing embryonic nervous system
We performed a partial functional screening of the kinome on a well-established embryonal tumor cell line (MON—a rhabdoid tumor cell line provided by Dr Delattre, Institut Curie, Paris France) [7,8,9] using lentiviral-CRISPR to target 160 individual kinase encoding genes representing the major branches of the human kinome and key isoforms within each branch
We demonstrated that inhibiting polo-like kinase 4 (PLK4) with the small-molecule inhibitor CFI-400945 (CAS#1338800-06-8) [12,13,14] resulted in impairment of proliferation, survival, migration and invasion in atypical teratoid/rhabdoid tumor (ATRT) and MB cell lines
Summary
Embryonal tumors of the central nervous system (CNS) are poorly differentiated tumors resembling the developing embryonic nervous system. We performed a partial functional screening of the kinome on a well-established embryonal tumor cell line (MON—a rhabdoid tumor cell line provided by Dr Delattre, Institut Curie, Paris France) [7,8,9] using lentiviral-CRISPR to target 160 individual kinase encoding genes representing the major branches of the human kinome and key isoforms within each branch. With this approach we identified the polo-like kinase 4 (PLK4) as a putative genetic hit. We established that polyploidy induced by PLK4 inhibition increased tumor cell susceptibility to DNA-damaging agents while sparing non-tumor cells [7,10]
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