Poster Presentation 25th Lorne Cancer Conference 2013

A novel murine model of lung cancer that facilitates acceleration of K-RasG12D driven tumourigensis  (#163)

Imogen Elsum 1 , Laura Yates 1 , Helen Pearson 1 , Humbert Patrick 1 2
  1. Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
  2. The Sir Peter MacCallum Department of Oncology, East Melbourne, Australia

Lung cancer is the leading cause of cancer deaths worldwide, largely due to detection at advanced stages of disease.  Genetic alterations are prevalent in lung cancer with activating mutations in K-Ras occurring in up to 30% of patients.  Constitutive activation of the Ras signalling network is essential for tumour maintenance and progression yet is typically coupled with deregulation of a secondary cellular process to drive invasion and metastasis.  Work from our laboratory has shown, similarly to what is observed in Drosophila, loss of the polarity protein Scribble cooperates with oncogenic Ras to promote mammalian tumour progression in vitro and in vivo 1 2 .   Here we show that aged heterozygous Scribble mice develop lung adenomas with 40% penetrance, suggesting Scribble depletion sensitises the lung to tumourigensis.  To more specifically assess the role of Scribble in lung cancer and increase clinical relevance, we crossed conditional Scribble knockout mice developed in our laboratory to the extensively characterised K-RasLSL-G12D lung tumour mouse model, where tumours are induced through intranasal inhalation of AdenoCre.  We found that Scribble deficiency cooperates with activated oncogenic K-Ras to promote tumour initiation and progression.  K-Ras driven lung tumours lacking Scribble expression, are more aggressive and of a higher grade than tumours induced by K-RasG12D alone.    Lungs of mice with both Scribble loss and activated oncogenic K-Ras show increased macrophage infiltration and hyperactivated MAPK-ERK and JNK signalling within tumours.  To determine the role of Scribble in human lung tumourigenesis, we are assessing metastasis through use of the human lung adenocarcinoma cell line A549.  In summary, we have developed a novel mouse model of lung cancer with Scribble as a regulator of the MAPK-ERK pathway.  We propose that Scribble mediated deregulation of signalling networks underlies accelerated tumour progression.

  1. Dow, L.E., Elsum, I.A., King, C.L., Kinross, K.M., Richardson, H.E., and Humbert, P.O. (2008). Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling. Oncogene 27, 5988-6001.
  2. Pearson, H.B., Perez-Mancera, P.A., Dow, L.E., Ryan, A., Tennstedt, P., Bogani, D., Elsum, I., Greenfield, A., Tuveson, D.A., Simon, R., et al. (2011). SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia. J Clin Invest 121, 4257-4267.