Editors' ChoiceCancer

Are Two Heads Really Better than One?

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Science Translational Medicine  12 Mar 2014:
Vol. 6, Issue 227, pp. 227ec46
DOI: 10.1126/scitranslmed.3008863

For oncogenes, perhaps two really is better than one. Cancer development and progression involve the sequential alteration of tumor suppressor and oncogene function, which allows for both the activation of growth-promoting pathways with inactivation of inhibitory signaling networks. Lung cancer remains the leading cause of cancer death worldwide. However, although a number of key therapeutically targetable genetic alterations that drive lung adenocarcinoma have been identified, the comparable drivers of squamous cell lung cancer have yet to be fully characterized. Justillien et al. report that protein kinase C1 (PRKCI) and SOX2 cooperate to drive a stem-like phenotype in lung squamous cell carcinoma and together drive tumorigenesis by establishing a cell-autonomous PKC-dependent Hedgehog (Hh) signaling axis.

The authors used an oncosphere assay and total RNA sequencing to identify three main PKC-regulated pathways—Wnt, Hh, and Notch—associated with stem cell maintenance. A small-molecule inhibitor of PKC signaling, auranofin, inhibited oncosphere proliferation in cell-based studies. Similar results were seen with inhibitors of Hh signaling pathways in this same experimental system. Moreover, cells transduced with RNA interference to various components of the PKC-HH signaling pathway exhibited altered orthotopic lung tumor initiation in vivo. Taken together, these data indicate that cell-autonomous PKC-dependent Hh signaling is critical for oncogenic tumorigenesis in vivo. Genomic analysis and subsequent functional validation identified amplification of SOX2 as being critical for the PKC-mediated oncosphere phenotype. Interestingly, both of these genes are coamplified in a substantial percentage of lung squamous cell carcinomas.

These studies identify a set of driver oncogenes in squamous cell lung cancer progression, highlight the virtues for cancer cells of cooperativitiy, and potentially define therapeutically targetable pathways for lung cancer treatment.

V. Justilien et al., The PRKCI and SOX2 oncogenes are coamplified and cooperate to activate Hedgehog signaling in lung squamous cell carcinoma. Cancer Cell 25, 139–151 (2014). [Abstract]

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