RAS-ERK signalling is central to epithelial tissue development, and deregulation potently drives tumour progression and invasion. How RAS-ERK is co-ordinately regulated with fundamental epithelial polarization programs is not yet clear.We have previously revealed using a powerful functional genomics screen, that the central cell polarity regulator and potent RAS inhibitor, SCRIB, is part of a large network of apicobasal polarity and asymmetric cell division (ACD) genes that together suppress RAS transformation, invasion and tumour progression. Depletion of this network promotes RAS transformation through spatiotemporal deregulation of ERK signalling, enhanced activity of AP-1 transcription factor FRA1, and potentiated IL-6-STAT3 signalling. In turn, the RAS oncogene targets key components of this network for deregulation by an ERK-FRA1 dependent transcriptional mechanism, revealing novel bi-directional cross-regulation between sustained RAS-ERK signalling and cell polarity and ACD networks. These findings are of potential significance regarding tumour cell heterogeneity, genomic instability, and acquired therapeutic resistance.
To directly assess if modulation of ERK signalling represents a common property of a broader epithelial polarity network, we have now conducted a high-content image-based siRNA screen, monitoring localized ERK activation. Comprehensive phenotypic cluster analysis identified a broad, yet highly specific role for diverse polarity sub-networks in the spatiotemporal modulation of sustained ERK signalling and we propose this property may be important for their tumour suppressive properties in human cancer. Concurrent assessment of localized SCRIB and β-catenin expression, an integral adherens junctions protein, has generated a powerful multidimensional dataset allowing precise functional mapping of the polarity network for maintenance of adhesion, polarized epithelial phenotypes, and spatial distribution of ERK signalling. Such systems-level, multi-parametric analyses allows generation of the functional and behavioural landscape of epithelial cells, and demonstrates potential to identify novel therapeutic strategies targeting functional networks, rather than individual genes, for the treatment of highly heterogeneous epithelial tumours.