Similar to LEIO, MFH-LEIO did not demonstrate any specific pattern of pathway activation compared to the rest of the samples.
However, non-responders showed a qualitatively similar dynamic pattern of pathway activity compared to age-matched responders.
These results indicated strong similarity between cell lines and tumours in the pattern of pathway enrichment (Fig 2).
Surprisingly we have found that the pattern of pathway utilisation in normal melanocytes was not distinct from those exhibited by the melanoma lines in the presence of serum.
Interestingly, similar to the patterns of overall gene expression, the pathways were also divided into two major pattern groups based on their activity and the top-ranked drugs in the Connectivity map also show a similar pattern of pathway activities.
The NRO pattern of pathway enrichment, in particular, shows a dramatic shift of emphasis between 30 and 60 minutes of activation including the turning on of genes in NFKB pathways (supplementary data) as predicted by our previous findings [ 30].
We believe that our studies could guide the development of prospective clinical studies that would evaluate the efficacy of therapeutic regimens, based on a combined pattern of pathway and chemosensitivity within a given subtype.
Taken together, the results indicate that all the analyzed human cells with de novo created trisomies and tetrasomies elicit a nearly identical pattern of pathway changes regardless of the identity of the supernumerary chromosome and the cell line.
This first global analysis of the transcriptional response in human cells with model complex aneuploidy reproduced the pattern of pathway changes observed in the tri- and tetrasomic cell lines.
Interestingly, it is also clear that an inverse pattern of pathway deregulation exists for HER1 and the SRC pathways, as well as for HER1 and RAS pathways within the Basal-like subtype, suggesting an opportunity to direct therapy, either HER1 specific, SRC specific, or RAS specific, as a function of these pathway profiles.
