Biology subjects

Kogner, P.

Publications and source records attributed to Kogner, P..

2 recordsLinked to original sources

bioRxiv2020

Malignant Schwann cell precursors mediate intratumoral plasticity in human neuroblastoma

Neuroblastoma is a heterogeneous embryonal malignancy and the most deadly tumor of childhood, although a minor subset may show spontaneous differentiation. It arises from the multipotent neural crest lineage during development. Some of this multipotency is retained in neuroblastoma, which can give rise to both adrenergic and mesenchymal tumor cells. The mechanisms enabling such dual fates are unknown, but likely help neuroblastoma to evade existing therapies. To understand neuroblastoma plasticity, we analyzed patient tumors using single-cell transcriptomics. In addition to the heterogeneous adrenergic and mesenchymal populations, we identify a subpopulation of malignant cells resembling Schwann cell precursors (SCPs). This SCP-like population connects the adrenergic and mesenchymal compartments through transitions structurally reminiscent of the SCP cell-fate decision fork that occurs during normal development. While the directionality of such transitions in neuroblastoma remains to be established, this finding expands the potential reservoirs of malignant cells, and suggests intratumoral plasticity mechanisms relevant for therapeutic resistance and relapse.

cancer biology↗

bioRxiv2019

Splicing-sensitive fusion transcripts associated with key tumor characteristics occur at high frequency in neuroblastoma

The paucity of recurrent mutations has hampered efforts to understand and treat neuroblastoma. Alternative splicing and splicing-dependent RNA-fusions represent mechanisms able to increase the gene product repertoire but their role in neuroblastoma remains largely unexplored. Through analysis of RNA-sequenced neuroblastoma we here show that elevated expression of splicing factors is a strong predictor of poor clinical outcome. Furthermore, we identified >900 primarily intrachromosomal fusions containing canonical splicing sites. Fusions included transcripts from well-known oncogenes, were enriched for proximal genes and in chromosomal regions commonly gained or lost in neuroblastoma. As a proof-of-principle that these fusions can generate altered gene products, we characterized a ZNF451-BAG2 fusion, generating a truncated BAG2-protein which inhibited retinoic acid-induced differentiation. Spliceosome inhibition impeded neuroblastoma fusion expression, induced apoptosis and inhibited xenograft tumor growth. Our findings elucidate a splicing-dependent mechanism producing altered gene products in neuroblastoma and suggest that the spliceosome is a tractable therapeutical target.

cancer biology↗