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Kalirin-RAC controls nucleokinetic migration in ADRN-type neuroblastoma

The migrational propensity of neuroblastoma is affected by cell identity, but the mechanisms behind the divergence remain unknown. Using RNAi and time-lapse imaging, we show that ADRN-type NB cells exhibit RAC1- and kalirin-dependent nucleokinetic (NUC) migration that relies on several integral comp...

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Main Authors: Afanasyeva, Elena (Author) , Gartlgruber, Moritz (Author) , Ryl, Tatsiana (Author) , Decaesteker, Bieke (Author) , Denecker, Geertrui (Author) , Mönke, Gregor (Author) , Toprak, Umut (Author) , Flórez, Andrés (Author) , Torkov, Alica (Author) , Dreidax, Daniel (Author) , Herrmann, Carl (Author) , Okonechnikov, Konstantin (Author) , Ek, Sara (Author) , Sharma, Ashwini Kumar (Author) , Sagulenko, Vitaliya (Author) , Speleman, Frank (Author) , Henrich, Kai-Oliver (Author) , Westermann, Frank (Author)
Format: Article (Journal)
Language:English
Published: 3 March, 2021
In: Life science alliance
Year: 2021, Volume: 4, Issue: 5, Pages: 1-25
ISSN:2575-1077
DOI:10.26508/lsa.201900332
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.26508/lsa.201900332
Verlag, lizenzpflichtig, Volltext: https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=DynamicDOIArticle&SrcApp=WOS&KeyAID=10.26508%2Flsa.201900332&DestApp=DOI&SrcAppSID=F5ufCNacAlsOyhPlCuO&SrcJTitle=LIFE+SCIENCE+ALLIANCE&DestDOIRegistrantName=Life+Science+Alliance
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Author Notes:Elena A Afanasyeva, Moritz Gartlgruber, Tatsiana Ryl, Bieke Decaesteker, Geertrui Denecker, Gregor Moenke, Umut H Toprak, Andres Florez, Alica Torkov, Daniel Dreidax, Carl Herrmann, Konstantin Okonechnikov, Sara Ek, Ashwini Kumar Sharma, Vitaliya Sagulenko, Frank Speleman, Kai-Oliver Henrich, Frank Westermann

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520 |a The migrational propensity of neuroblastoma is affected by cell identity, but the mechanisms behind the divergence remain unknown. Using RNAi and time-lapse imaging, we show that ADRN-type NB cells exhibit RAC1- and kalirin-dependent nucleokinetic (NUC) migration that relies on several integral components of neuronal migration. Inhibition of NUC migration by RAC1 and kalirin-GEF1 inhibitors occurs without hampering cell proliferation and ADRN identity. Using three clinically relevant expression dichotomies, we reveal that most of up-regulated mRNAs in RAC1- and kalirin-GEF1-suppressed ADRN-type NB cells are associated with low-risk characteristics. The computational analysis shows that, in a context of overall gene set poverty, the upregulomes in RAC1- and kalirin-GEF1-suppressed ADRN-type cells are a batch of AU-rich element-containing mRNAs, which suggests a link between NUC migration and mRNA stability. Gene set enrichment analysis-based search for vulnerabilities reveals prospective weak points in RAC1- and kalirin-GEF1-suppressed ADRN-type NB cells, including activities of H3K27- and DNA methyltransferases. Altogether, these data support the introduction of NUC inhibitors into cancer treatment research. 
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