Prof Owen Sansom FRSE, FMEDSci - Colorectal Cancer and Wnt Signalling

Introduction

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Colorectal cancer (CRC)—the third most common cancer in the UK and the second leading cause of cancer mortality—is a heterogeneous disease comprising distinct molecular subgroups that differ in their histopathological features, prognosis, and response to therapy. Despite advances in the detection and treatment of early-stage disease, patients with advanced, recurrent, or metastatic CRCs have few therapeutic options and a dismal prognosis. Utilising state-of-the-art preclinical models harbouring key driver mutations, our group is interrogating the molecular mechanisms underpinning CRC initiation, progression, response to therapy, and metastasis. Our overarching goals are to identify early-stage diagnostic biomarkers and develop stage- and subtype-specific targeted therapies.
As part of these efforts, we are major contributors to a number of large cancer consortia, with the aim of driving more effective therapeutic approaches in colorectal cancer. Our group leads a Europe-wide, CRUK-funded consortium of basic, translational, and clinical scientists (ACRCelerate—Colorectal Cancer Stratified Medicine Network) to identify new therapeutic targets for the different CRC subtypes and deliver molecular insights with the potential to inform clinical decision-making and patient stratification. Similarly, through participation in the CRUK Grand Challenge Rosetta consortium, we are working to therapeutically exploit the altered metabolic dependencies of oncogene-addicted CRCs, and determine how distinct tumour metabolic profiles can confer resistance or predict sensitivity to standard-of-care or novel targeted therapies. Moreover, as a key contributor to the CRUK Grand Challenge SpecifiCancer consortium, we are employing transcriptional, epigenetic, and proteomic approaches to understand why there are tissue- and cell type-specific differences in the response to oncogenic mutations, with the aim of developing methods to suppress the impact of these mutations in cancer.
In addition, we are partnering with a number of leading industry innovator to accelerate the path from bench to bedside. For example, in partnership with Novartis, we are working towards the development of novel KRAS inhibitors, to address a pressing clinical need in colorectal cancer.

Want to find out more about Professor Sansom's work?

Read about his 2009 Nature paper on the CRUK science blog and listen to him talking about bowel cancer stem cells.

See a Google Hangout on the subject of red meat and cancer featuring Owen Sansom and Kathryn Bradbury from the University of Oxford: https://www.youtube.com/watch?v=jS1QW74wJRw

Other funding:

Lab Report

Sansom Lab Report (450 KB)

Key Publications

Jackstadt R, van Hooff SR, Leach JD, Cortes-Lavaud X, Lohuis JO, Ridgway RA, Wouters VM, Roper J, Kendall TJ, Roxburgh CS, Horgan PG, Nixon C, Nourse C, Gunzer M, Clark W, Hedley A, Yilmaz OH, Rashid M, Bailey P, Biankin AV, Campbell AD, Adams DJ, Barry ST, Steele CW, Medema JP, Sansom OJ. Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis. Cancer cell. 2019; 36: 319-336.e317.

Johansson J, Naszai M, Hodder MC, Pickering KA, Miller BW, Ridgway RA, Yu Y, Peschard P, Brachmann S, Campbell AD, Cordero JB, Sansom OJ. RAL GTPases Drive Intestinal Stem Cell Function and Regeneration through Internalization of WNT Signalosomes. Cell Stem Cell. 2019; 24: 592-607.e7.

Faller WJ, Jackson TJ, Knight JR, Ridgway RA, Jamieson T, Karim SA, Jones C, Radulescu S, Huels DJ, Myant KB, Dudek KM, Casey HA, Scopelliti A, Cordero JB, Vidal M, Pende M, Ryazanov AG, Sonenberg N, Meyuhas O, Hall MN, Bushell M, Willis AE, Sansom OJ. mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature. 2014; 517: 497–500

Myant KB, Cammareri P, McGhee EJ, Ridgway RA, Huels DJ, Cordero JB, Schwitalla S, Kalna G, Ogg EL, Athineos D, Timpson P, Vidal M, Murray GI, Greten FR, Anderson KI, Sansom OJ. ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell Stem Cell. 2013; 12: 761-73

Ashton GH, Morton JP, Myant K, Phesse TJ, Ridgway RA, Marsh V, Wilkins JA, Athineos D, Muncan V, Kemp R, Neufeld K, Clevers H, Brunton V, Winton DJ, Wang X, Sears RC, Clarke AR, Frame MC, Sansom OJ. Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling. Dev Cell. 2010; 19: 259-69

Morton JP, Timpson P, Karim SA, Ridgway RA, Athineos D, Doyle B, Jamieson NB, Oien KA, Lowy AM, Brunton VG, Frame MC, Evans TR, Sansom OJ. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc Natl Acad Sci USA. 2010; 107: 246-51

Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, Danenberg E, Clarke AR, Sansom OJ, Clevers H. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 2009 457: 608-11

Sansom OJ, Meniel VS, Muncan V, Phesse TJ, Wilkins JA, Reed KR, Vass JK, Athineos DA, Clevers H, Clarke AR. c-Myc deletion rescues Apc deficiency in the small intestine. Nature. 2007; 446: 676-9

Sansom OJ, Reed KR, Hayes AJ, Ireland H, Brinkmann H, Newton IP, Batlle E, Simon-Assmann P, Clevers H, Nathke IS, Clarke AR, Winton DJ. Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev. 2004; 18: 1385-90