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Marc de la Roche

Oncogenic Wnt signaling in cancer

The molecular aetiology of colorectal cancer (CRC) is well known: the mutant, oncogenic form of the Wnt signaling pathway drives the malignant transformation of intestinal epithelial stem cells leading to tumorigenesis. The primary research interests of the lab are to uncover essential regulatory nodes within oncogenic Wnt signaling.

At the core of the research programme are two tractable models of CRC to analyze roles for cellular signaling pathways, in particular the oncogenic Wnt signaling pathway. One of these models is a genetically engineered mouse (GEM) to model CRC, a disease that currently lacks suitable in vivo models. Importantly, this GEM encompasses the genetically coded ability to inducibly inhibit oncogenic Wnt signaling in tumours.

We are also interested in the role of the tumour suppressor adenomatous polyposis coli (APC) in CRC etiology. In addition to Wnt pathway regulation, APC plays a key role in maintaining epithelial cell polarity. Mutational inactivation of APC, the root cause of intestinal epithelial tumour development, may therefore compromise both Wnt pathway regulation and epithelial cell- and tissue-polarity. We are examining these APC-mediated functions using organotypic epithelial cultures to understand their involvement in preventing tumorigenesis.

Lab members: Thomas Foets, Helena Rannikmae, Heidi Funke

Key publications:

1. de la Roche M, Ibrahim AE, Mieszczanek J, Bienz M. LEF1 and B9L shield beta-catenin from inactivation by Axin, desensitizing colorectal cancer cells to tankyrase inhibitors. Cancer research. 2014;74(5):1495-505. Abstract

2. de la Roche, M, Rutherford, T, Gupta, D, Veprintsev, DB, Saxty, B, Freund, SM and Bienz, M. (2012) An intrinsically labile alpha-helix abutting the BCL9-binding site of beta-catenin is required for its inhibition by carnosic acid. Nature Comms. 21;3:680 Abstract

3. de la Roche, M, Worm, J, and Bienz, M. (2008) The function of BCL9 in Wnt/beta-catenin signalling and colorectal cancer cells. BMC Cancer. 15(8):199 Abstract