Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Tracking of Melanoma Cell Plasticity by Transcriptional Reporters

Version 1 : Received: 21 December 2021 / Approved: 22 December 2021 / Online: 22 December 2021 (15:04:59 CET)
Version 2 : Received: 12 January 2022 / Approved: 13 January 2022 / Online: 13 January 2022 (12:43:21 CET)

A peer-reviewed article of this Preprint also exists.

Vidal, A.; Redmer, T. Tracking of Melanoma Cell Plasticity by Transcriptional Reporters. Int. J. Mol. Sci. 2022, 23, 1199. Vidal, A.; Redmer, T. Tracking of Melanoma Cell Plasticity by Transcriptional Reporters. Int. J. Mol. Sci. 2022, 23, 1199.

Journal reference: Int. J. Mol. Sci. 2022, 23, 1199
DOI: 10.3390/ijms23031199

Abstract

Clonal evolution and cellular plasticity are the genetic and non-genetic driving forces of tumor heterogeneity that in turn determines the tumor cell response towards therapeutic drugs. Sever-al lines of evidence suggest that therapeutic interventions foster the selection of drug resistant neural crest stem-like cells (NCSCs) that establish minimal residual disease (MRD) in melano-ma. Here we established a dual reporter system enabling the tracking of NGFR expression and mRNA stability, providing insights into the maintenance of NCSC-states. We observed that the transcriptional reporter that contained a 1kb fragment of the human NGFR promoter was acti-vated only in a minor subset (0.72±0.49%, range 0.3-1.5) and ~2-4% of A375 melanoma cells re-vealed stable NGFR mRNA. The combination of both reporters provided insights into pheno-type switching and revealed that both cellular subsets gave rise to cellular heterogeneity. Moreover, whole transcriptome profiling and gene set enrichment analysis (GSEA) of the minor cellular subset revealed hypoxia-associated genes serving as potential drivers of a NGFR-associated phenotype switching in vitro and in relapsed, post-BRAF inhibitor treated tu-mors. Concordantly, we observed that the minor cellular subset increased in response to dabrafenib over time. In summary, our reporter-based approach provided insights into plastici-ty and identified a cellular subset that might be responsible for the establishment of MRD in melanoma.

Keywords

Transcriptional reporters 1; Plasticity 2; Stemness 3; NGFR 4

Subject

LIFE SCIENCES, Cell & Developmental Biology

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