Oral Presentation 2014 Cutaneous Biology Meeting

The polarity regulator SCRIB plays a tumour suppressive role in DMBA/TPA-induced squamous cell carcinoma (#11)

Helen B Pearson 1 2 , Holger Schluter 3 , Toby J Phesse 4 , Edwina McGlinn 5 , Andrew Ryan 6 , Anuratha Srikumar 1 , Nathan Godde 1 , Matthias Ernst 4 , Pritinder Kaur 2 3 , Patrick Humbert 1 2
  1. Cell Cycle and Cancer Genetics Lab, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, Melbourne University, Melbourne, VIC, Australia
  3. Epithelial Stem Cell Biology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
  4. Cell Signalling and Cell Death, The Walter and Eliza Hall Institute, Melbourne, VIC, Australia
  5. Australian Regenerative Medicine Institute, Monash University , Clayton, VIC, Australia
  6. TissuPath Laboratories, Melbourne, VIC, Australia

The cell polarity network mediates diverse signalling cascades to coordinate tissue architecture, migration, proliferation and asymmetric cell division during development and is required for the maintenance of epithelial tissue homeostasis in adult tissues1,2. Loss of cell polarity is a frequent characteristic of all epithelial cancers, suggesting a crucial role for polarity mediators in suppressing tumorigenesis1,2. Indeed, deregulation of the polarity regulator SCRIB has been correlated to multiple human epithelial cancers, including prostate, colon, breast and endometrial3-5. 

Here we identify the core polarity protein Scrib is required for temporal control of the epidermal permeability barrier and is a potent tumor suppressor of squamous cell carcinoma (SCC) in mice. Embryonic analysis of neonatal lethal Scrib knockout mice revealed a 24 h delay in epidermal permeability barrier formation, associated with impaired keratinocyte maturation. In addition, conditional bi-allelic depletion of Scrib in adult murine epidermis is not sufficient to disrupt epidermal homeostasis. Nevertheless, Scrib deficiency significantly promoted tumor multiplicity and SCC progression in the context of DMBA/TPA-induced epidermal carcinogenesis. Assessment of the proliferation marker BrdU by immunohistochemistry revealed a significant increase in the number of BrdU positive nuclei in Scrib depleted DMBA/TPA-induced lesions compared to WT controls. Together these data indicate that although Scrib is not required to maintain murine epidermal homeostasis, Scrib depletion can promote SCC formation and progression by elevating proliferation in the context of additional clinically relevant oncogenic events. Furthermore, our novel model provides a beneficial tool to delineate the molecular events employed by the polarity network to suppress SCC growth.

  1. Dow, L.E. and P.O. Humbert, Polarity regulators and the control of epithelial architecture, cell migration, and tumorigenesis. Int Rev Cytol, 2007. 262: p. 253-302.
  2. Humbert, P.O. et al., Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module. Oncogene, 2008. 27(55):6888-6907.
  3. Zhan, L., et al., Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma. Cell, 2008. 135(5): p. 865-78.
  4. Pearson, H.B. et al., SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia. J Clin Invest. 2011;121(11):4257–4267.
  5. Godde, N et al, Scribble Modulates the MAPK/Fra1 Pathway to Disrupt Luminal and Ductal Integrity and Suppress Tumour Formation in the Mammary Gland. PLoS Genetics, 2014; 10(5): e1004323.