Intercellular extrachromosomal DNA copy number heterogeneity drives cancer cell state diversity

Stoeber, M. C.; Chamorro Gonzalez, R.; Brueckner, L.; Conrad, T.; Wittstruck, N.; Szymansky, A.; Eggert, A.; Schulte, J. H.; Koche, R. P.; Henssen, A. G.; Schwarz, R. F.; Haase, K.

doi:10.1101/2023.01.21.525014

bioRxiv · 10.1101/2023.01.21.525014

Intercellular extrachromosomal DNA copy number heterogeneity drives cancer cell state diversity

Stoeber, M. C.·Chamorro Gonzalez, R.·Brueckner, L.·Conrad, T.·Wittstruck, N.·Szymansky, A.·Eggert, A.·Schulte, J. H.·Koche, R. P.·Henssen, A. G.·Schwarz, R. F.·Haase, K.

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Abstract

Neuroblastoma is characterised by extensive inter- and intra-tumour genetic heterogeneity and varying clinical outcomes. One possible driver for this heterogeneity are extrachromosomal DNAs (ecDNA), which segregate independently to the daughter cells during cell division and can lead to rapid amplification of oncogenes. While ecDNA-mediated oncogene amplification has been shown to be associated with poor prognosis in many cancer entities, the effects of ecDNA copy number heterogeneity on intermediate phenotypes are still poorly understood. Here, we leverage DNA and RNA sequencing data from the same single cells in cell lines and neuroblastoma patients to investigate these effects. We utilise ecDNA amplicon structures to determine precise ecDNA copy numbers and reveal extensive intercellular ecDNA copy number heterogeneity. We further provide direct evidence for the effects of this heterogeneity on gene expression of cargo genes, including MYCN and its downstream targets, and the overall transcriptional state of neuroblastoma cells. These results highlight the potential for rapid adaptability of cellular states within a tumour cell population mediated by ecDNA copy number, emphasising the need for ecDNA-specific treatment strategies to tackle tumour formation and adaptation.

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Stoeber, M. C., Chamorro Gonzalez, R., Brueckner, L., Conrad, T., Wittstruck, N., Szymansky, A., Eggert, A., Schulte, J. H., Koche, R. P., Henssen, A. G., Schwarz, R. F., Haase, K.. 2023-01-21. Intercellular extrachromosomal DNA copy number heterogeneity drives cancer cell state diversity. https://doi.org/10.1101/2023.01.21.525014

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