Vivian Li group

Wnt signalling pathway, intestinal stem cells and cancer

The WNT signalling pathway controls myriad biological phenomena throughout development and adult life of all animals. The Wnt pathway plays a dual role in the intestine: it maintains crypt stem cell compartments and, when activated by mutation, it is the cause of colon cancer. Our goal is to understand Wnt pathway regulation in both aspects of intestinal biology.

We will use mouse models to study human colorectal cancer in vivo. We combine the strength of basic (molecular approaches and mouse genetics) and clinical cancer research to answer important biological questions. We are also experts in the use of state-of-the-art organoid culture technique. These organoids, also called “mini-guts”, grow 3-dimensionally in matrigel over long time-periods to form intestinal crypt-villus budding structures encompassing all cellular lineages. We can genetically modify the organoids and study the morphological changes in vitro. This presents which a superior physiological readout compared to classical cell lines.

Morphologies of intestinal organoids

Morphologies of intestinal organoids

Click image to view at full-size

Morphologies of intestinal organoids derived from normal and Apc-deleted mice.

Wnt signal regulation and intestinal stem cell maintenance

In the adult intestine, crypts constitute the stem/progenitor cell compartments responsible for self-renewal of the epithelium. Wnt signals occur at the bottoms of proliferative crypts, the stem cell zone. This generates a signalling gradient from the stem cell zone to the upper trans-amplifying (TA) cells at the crypt-villus junction. Wnt signalling activates many downstream target gene transcriptions, yet Wnt target genes come in two flavours: 'crypt-gradient' and 'stem-cell restricted'. The underlying question is how the expression of stem cell-specific Wnt targets is restricted to stem cells. We investigate the molecular control mechanism that fine-tunes the expression pattern of the Wnt/Stem cell-signature genes.

Crypt-gradient or stem cell-restricted patterns

Crypt-gradient or stem cell-restricted patterns

Click image to view at full-size

Wnt target genes are expressed either in crypt-gradient (left) or in stem cell-restricted (right) patterns.

Wnt pathway activation in colorectal cancers

Loss of the negative Wnt pathway regulator APC occurs in the majority of colorectal cancers. We have previously described a novel molecular mechanism of Wnt pathway activation. We have found that β-catenin is not only phosphorylated inside the Axin1 complex, but is also ubiquitinated and degraded via the proteasome, all within an intact Axin1 complex. In contrast to current views, we find neither a disassembly of the complex nor an inhibition of phosphorylation of Axin1-bound β-catenin upon Wnt signalling. Instead, Wnt signalling suppresses β-catenin ubiquitination normally occurring within the complex, leading to complex saturation by accumulated phospho-β-catenin.

Schematic diagrams

Schematic diagrams

Click image to view at full-size

Schematic diagrams showing our novel Wnt activation mechanism (Li et al, Cell, 2012).

We further show that APC truncation in colorectal cancers, instead of causing complex dissociation, abolishes Axin-bound-β-catenin ubiquitination in colorectal cancers. Despite the crucial role of APC in tumour initiation, the oncogenic mechanism of APC truncation in Wnt pathway activation remains unclear. Our goal is to investigate the mechanism of how APC mediates β-catenin ubiquitination in the destruction complex using colorectal cancer as a model.

In an independent research line, we aim to characterize the mechanism of Wnt pathway activation in a subgroup of colorectal cancer with wild-type APC and Microsatellite-Instability. This subtype, characterized by hypermutation due to genetic instability, might eventually obtain mutations in the Wnt pathway components such as β-catenin and Axin2.

A recent study based on Whole Genome Sequencing of a large cohort of colorectal cancers, however, shows that β-catenin and Axin mutations occur only in a small number of the Microsatellite-Instability cases. We aim to further explore the Wnt-activating mechanism in Microsatellite-Instability colon cancer by generating conditional knock-in/knockout mice for candidate genes, identified by whole genome-analyses of human colorectal cancer cases.

Selected publications

Our research themes

Click links to view others working on these themes

Top of page

© MRC National Institute for Medical Research
The Ridgeway, Mill Hill, London NW7 1AA