Flash Talk & Poster Presentation 32nd Lorne Cancer 2020

Identifying co-operative drivers and novel therapeutic targets in SMAD4-deficient oesophageal adenocarcinoma (#105)

Julia V Milne 1 2 , Kenji M Fujihara 1 2 , Jovana R Gotovac 1 2 , Kaylene Simpson 1 2 3 , Wayne A Phillips 1 2 4 , Nicholas J Clemons 1 2
  1. Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VICTORIA, Australia
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VICTORIA, Australia
  3. Victorian Centre for Functional Genomics (VCFG), Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  4. Department of Surgery (St. Vincent's Hospital), University of Melbourne, Parkville, Victoria, Australia

Oesophageal cancer is the 8th most common cancer worldwide and has the 6th highest mortality rate of all cancers. The 5-year survival rate following oesophageal adenocarcinoma (OAC) diagnosis is dismal at <15%, indicating a dire need for improved therapeutic strategies and early detection. OAC develops stepwise following exposure to chronic gastric reflux: From pre-malignant Barrett’s metaplasia through low- and high-grade dysplasia to invasive cancer. Mutation or loss of common tumour suppressor genes TP53 and SMAD4 act as markers for cancer progression, occurring in high-grade dysplastic tissue and invasive OAC, respectively. Our group have established a novel in vivo tumourigenesis model for progression of Barrett’s metaplasia to OAC, in which SMAD4-deficient Barrett’s metaplasia cells form tumours in immunodeficient mice after a period of latency and in a dose-dependent manner. This delayed tumour growth onset suggests further genomic changes required for oncogenesis. Our finding that increased copy number alterations co-occur with SMAD4 deficiency strengthens this and suggests that SMAD4 may play a role in maintaining genomic stability. This work aimed to identify and validate novel therapeutic targets as well as co-operative drivers of tumourigenesis for SMAD4-deficient oesophageal adenocarcinoma. We have conducted simultaneous genome-wide CRISPR-Cas9 knockout synthetic lethality and tumourigenesis screens in both in vitro and in vivo settings with a background of SMAD4 wildtype and knockout cells. Our in vivo tumourigenesis screen produced tumours 4-fold faster than the previous model and promises to identify cooperative drivers of tumourigenesis in SMAD4-deficient OAC. The synthetic lethality screen has identified numerous potential therapeutic targets, both novel and clinically relevant, for SMAD4-deficient OAC. The identification of genes and pathways that co-operate with SMAD4 deficiency in pre-malignant cells to promote tumourigenesis will allow for improved patient screening and inform future treatment options. Additionally, the identification of genes and pathways that are essential in SMAD4-deficient tumours will unveil new potential treatment targets for SMAD4-deficient cancers.

  1. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., and Jemal, A. (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68, 394-424
  2. Wild, C. P., and Hardie, L. J. (2003) Reflux, Barrett's oesophagus and adenocarcinoma: burning questions. Nat Rev Cancer 3, 676-684
  3. Weaver, J. M. J., Ross-Innes, C. S., Shannon, N., Lynch, A. G., Forshew, T., Barbera, M., Murtaza, M., Ong, C. J., Lao-Sirieix, P., Dunning, M. J., Smith, L., Smith, M. L., Anderson, C. L., Carvalho, B., O'Donovan, M., Underwood, T. J., May, A. P., Grehan, N., Hardwick, R., Davies, J., Oloumi, A., Aparicio, S., Caldas, C., Eldridge, M. D., Edwards, P. A. W., Rosenfeld, N., Tavare, S., Fitzgerald, R. C., and consortium, O. (2014) Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis. Nat Genet 46, 837-843
  4. Siegel, R. L., Miller, K. D., and Jemal, A. (2016) Cancer statistics, 2016. CA Cancer J Clin 66, 7-30