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Department of Biochemistry

 
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The Wnt pathway in normal homeostasis and disease.

 

The Wnt pathway is an intracellular series of events culminating on a gene expression program that regulates various biological outcomes. One such outcome is stem cell multipotency in the intestinal epithelia, a function responsible for the maintenance of a well-ordered monolayer of different cell types in a tissue roughly the area of an ice hockey rink. ​Oncogenic mutations in the Wnt pathway that are commonly found in colon cancer lead to spurious cell outgrowths equating to bumps in the surface of this ice rink – these are intestinal epithelial tumours. If the bumps are allowed to develop further oncogenic mutations, they may develop into colon cancer. Our laboratory is geared towards finding ways to prevent both the acquisition of tumours and the development of cancer.

Our research uses representative examples of the intestinal epithelia called organoids that we can: (i) grow in a tube and manipulate; and (ii) introduce specific oncogenic mutations or get rid of pre-existing ones. Through the use of organoids, we are identifying and modulating molecular circuitry with the goal of enforcing normal intestinal epithelial homeostasis.

 

Research objectives

  • Determine why the intestinal epithelia is particularly vulnerable to oncogenic mutations in the tumour suppressor APC.

  • Define whether the oncogenic form of the Wnt pathway is a bone fide therapeutic target in colon cancer.

  • Molecular and clinical characterization of a subset of colon cancer stratified by specific mutations in TCF7L2.

 

Key publications

Farooqi AA, de la Roche M, Djamgoz MBA, Siddik ZH (2019). Overview of the oncogenic signalling pathways in colorectal cancer: mechanistic insights. Semin. Cancer Biol., 58:65-79. doi: 10.1016/j.semcancer.2019.01.001

Urbischek M, Rannikmae H, Foets T, Ravn K, Hyvönen M, de la Roche M (2019). Organoid culture media containing growth factors of defined cellular activity. Sci. Rep., 9(1):6193. doi: 10.1038/s41598-019-42604-0

Xu W, Lau YH, Fischer G, Tan YS, Chattopadhyay A, de la Roche M, Hyvönen M, Verma C, Spring DR, Itzhaki LS (2017). Macrocyclized extended peptides: inhibiting the substrate-recognition domain of tankyrase. J. Am. Chem. Soc., 139(6):2245-2256. doi: 10.1021/jacs.6b10234

de la Roche M, Ibrahim AE, Mieszczanek J, Bienz M (2014). LEF1 and B9L shield b-catenin from inactivation by axin, desensitizing colorectal cancer cells to tankyrase inhibitors. Cancer Res., 74(5):1495-1505.​ doi: 10.1158/0008-5472.CAN-13-2682

de la Roche M, Rutherford T, Gupta D, Veprintsev DB, Saxty B, Freund SM, Bienz M (2012). An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid. Nat. Commun., 3:680. doi: 10.1038/ncomms1680

Contact details

Research Group Leader  Marc de la Roche​

Email  mad58@cam.ac.uk

Location  Sanger Building

Opportunities

The de la Roche Group is accepting enquiries from prospective interns, undergraduate students, postgraduate students and postdoctoral researchers.