Rewiring of human lung cell lineage and mitotic networks in lung adenocarcinomas
Nature Communications 4, Article number: 1701 / doi:10.1038/ncomms2660
Received 15 June 2012 / Accepted 26 February 2013 / Published 16 April 2013
Analysis of gene expression patterns in normal tissues and their perturbations in tumours can help to identify the functional roles of oncogenes or tumour suppressors and identify potential new therapeutic targets. Here, gene expression correlation networks were derived from 92 normal human lung samples and patient-matched adenocarcinomas. The networks from normal lung show that NKX2-1 is linked to the alveolar type 2 lineage, and identify PEBP4 as a novel marker expressed in alveolar type 2 cells. Differential correlation analysis shows that the NKX2-1 network in tumours includes pathways associated with glutamate metabolism, and identifies Vaccinia-related kinase (VRK1) as a potential drug target in a tumour-specific mitotic network. We show that VRK1 inhibition cooperates with inhibition of poly (ADP-ribose) polymerase signalling to inhibit growth of lung tumour cells. Targeting of genes that are recruited into tumour mitotic networks may provide a wider therapeutic window than that seen by inhibition of known mitotic genes.
This work was supported by grants from The Bonnie J. Addario Lung Cancer Foundation (to A.B. and D.J.), the National Cancer Institute U01 CA84244 and RO1 CA111834-01 (to A.B.) and the UALC (Uniting Against Lung Cancer) foundation (to I.-J.K.).