Fig. 1: Hypomethylation of pericentromeric satellite repeats correlates with etoposide resistance in non-small cell lung cancer PDX mouse models.

A Volcano plot shows the global methylation changes at repetitive elements between 22 patient-derived NSCLC xenograft tumor samples and their corresponding normal tissue (TvsN). Each dot represents one repetitive element, based on the RepeatMasker database, classified into subclasses (color code). The log fold change of methylation in tumor versus normal tissue is plotted on the x-axis, the y-axis shows the negative log 10 of the p-value. B Heatmap shows the Pearson’s correlation between the sensitivity of the PDXs (measured by the differential methylation between tumor and normal tissues) with the chemotherapeutics indicated by the column name. The adjacent bar indicates the repetitive region class. C Composition of the significantly correlated (p-value < 0.05) repeats classes: positive (left) and negative (right) correlations between response to Etoposide and differential methylation. D Methylation levels of two etoposide sensitive PDXs (7166 and 7298; green) and two etoposide resistant PDX models (7433 and 7466; red) at the Satellite III DNA locus on chromosome 9. Lighter colors represent the coverage of normal tissue (N), darker colors show the coverage of tumor samples (T). E RNA FISH staining of Satellite III transcripts (SatIII RNA) in FFPE tumor material of untreated etoposide resistant (7433) and etoposide sensitive (10395) PDX mice. The tissue was stained with SatIII RNA FISH probes (red) as well as Hoechst stain 33342 (blue). Scale bar, 10 µm. F Correlation of SatIII RNA foci and the relative tumor volume on native FFPE PDX tumor tissue. SatIII RNA foci were stained with SatIII RNA FISH, quantified, and set into relation to the response rate towards etoposide.