Kalirin-RAC controls nucleokinetic migration in ADRN-type neuroblastoma

Abstract

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.

SOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry

“…4c, d, S4e). In line with this, Afanasyeva et al demonstrated decreased migration upon SOX11 knockdown in IMR-32 spheroids, further showing that SOX11 knockdown fosters morphological asymmetric cell divisions and causes reprogramming of nucleokinesis migration in ADRN-type NB cells 19 . To functionally validate the predicted role in control of cytoskeleton and cell migration by our SOX11 overexpression RNA-sequencing data, we performed woundhealing assays confirming that SOX11 overexpression enhances wound healing capacity and migration potential in SH-EP NB cells (Supplementary Fig.…”

From DNA Copy Number Gains and Tumor Dependencies to Novel Therapeutic Targets for High-Risk Neuroblastoma

“…Indeed, SOX11 is regulated by multiple adrenergic specific cis-acting (super-) enhancers, along with adrenergic NBs being strongly dependent on high SOX11 expression levels for growth and proliferation [111]. SOX11 was also shown to be involved in nucleokinesis in adrenergic NB cells [112]. We identified and validated functional SOX11 target genes through genome-wide DNA-binding and transcriptome analysis and identified several genes which are implicated in chromatin remodeling and epigenetic modification.…”

“…Re-analysis of NB DNA copy number profiling data revealed the sympatho-adrenal lineage specific SOX11 gene in recurrent chromosome 2p focal gains and amplifications [111]. SOX11 is specifically expressed in adrenergic NBs and absent in mesenchymal NBs [111,112], two distinct superenhancer associated subtypes in NB [135,136]. Indeed, SOX11 is regulated by multiple adrenergic specific cis-acting (super-) enhancers, along with adrenergic NBs being strongly dependent on high SOX11 expression levels for growth and proliferation [111].…”