IBCS seminar - "Investigating driver oncogenes and tumour suppressor genes in vivo for potential personalised/stratified medicine approaches."

About the speaker:

Owen Sansom is interim director of the Cancer Research UK Beatson Institute, Glasgow. Owen gained his PhD in 2001 working on in vivo models of apoptosis in cancer. Since then, Owen has been instrumental in determining the molecular hallmarks of colorectal cancer (CRC), including showing the roles of the tumour suppressor protein APC and the WNT signalling pathway and the involvement of intestinal stem cells in tumourigenesis. In 2005, Owen established his own laboratory at the Cancer Research UK Beatson Institute, where he became deputy director in 2010. The Sansom laboratory uses in vivo models and 3D in vitro models to recapitulate CRC and pancreatic cancer to investigate the molecular mechanisms underpinning tumourigenesis and to identify novel drug targets. In 2007 Owen won the BACR/AstraZeneca Young Scientist Frank Rose Award and in 2012 was elected a Fellow of the Royal Society of Edinburgh and was awarded the Cancer Research UK Future Leaders in Cancer Research prize.

Research portfolio:

My laboratory focuses on the role of Wnt signalling in intestinal homeostasis, regeneration and cancer. Much of our work has investigated how the requirement for Wnt signalling target genes alters during regeneration and cancer. Thus my laboratory has shown the Wnt signalling drives both regeneration and cancer through the c-Myc transcription factor. We have shown the basic biology of why MTOR is a limiting factor downstream of Wnt signalling activation via the control of translational elongation. It is interesting to note that both MYC reduction and MTORC1 inhibition (via rapamycin) are two  “bona fide” ways to increase lifespan.

Through lineage tracing experiments we have shown that Lgr5+ intestinal stem cells act as a very efficient cell of origin for CRC. Non stem cells can be transformed but that requires additional factors such as inflammation and/or additional oncogenic mutations.  We are able to transduce stem cells ex vivo using lentiviral vectors. We also have cre lines which target stem cell and differentiated cells that allow us to test the relative transformation of different populations both in vivo and in vitro. More recently we have CRISPR technology up and running in vitro.

Our work necessitates us to closely examine the normal intestine and we investigated how homeostasis, mutational load, clonogenicity,  clonal dominance/stem cell competition are altered by the genes that are commonly altered in colon cancer and by drugs targeting these pathways.  We have considerable experience therefore in seeing how these mutations alter stem cell properites and expression through stem cell sorting.

Over the past 5 years we have also optimised intestinal “ex vivo” approaches (the so-called organoid models) and have a bank of mouse derived lines from wild type crypts to adenoma and adenocarcinoma. We have used these organoids to examine clonal dominance in vitro and long term clonogenic capacity. The ability to manipulate these in vitro (lentiviral, CRISPR) and then transplant in vivo also gives us the ability to test the consequences of gene manipulation in vivo.

A list of future speakers can be found at:

http://medicine.exeter.ac.uk/events/ibcsseminarseries/