Vivian Li

Stem Cell and Cancer Biology Laboratory

Wnt signalling is a highly conserved pathway that plays principle roles in stem cell biology and in cancer. For both, the intestine has emerged as a prime experimental model. In the adult intestine, it is well established that Wnt signalling plays complementary roles in physiology and pathology: it maintains crypt stem cell compartments and when activated by mutation, it is the cause of colon cancer. We study how the Wnt pathway is regulated in intestinal stem cell and cancer development. Our goal is to translate the basic stem cell research to the clinic to aid cancer treatment and regenerative medicine.

We use a broad range of research tools to study how intestinal stem cells are regulated and how the Wnt pathway is activated in colorectal cancer. We have various mouse models to study intestinal tissue homeostasis and colorectal cancer in vivo.

We also culture intestinal organoids in vitro for functional studies and for drug screening. These organoids, also called "mini-guts", grow 3-dimensionally in matrigel over long time-periods to form intestinal crypt-villus budding structures with full self-renewal and differentiative potential.

We can genetically modify the organoids for functional studies in vitro. This presents a superior physiological readout compared to classical mono-layer cell line culture.

Highly proliferative intestinal organoid.

Highly proliferative intestinal organoid. Intestinal orgnaoid with Ki67 (green) staining. (Click to view larger image)

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'. We are interested to study how the expression of stem cell-specific Wnt targets is regulated. We investigate the molecular mechanism that controls the expression pattern of these stem cell-expressing Wnt target genes, which might shed light on the mechanism that defines intestinal stem cell spatial positioning.

Crypt-gradient or stem cell-restricted patterns.

Crypt-gradient or stem cell-restricted patterns. (Click to view larger image)

Wnt activating mechanism in colorectal cancers

Loss of the negative Wnt pathway regulator APC occurs in the majority of colorectal cancers (CRC).

We have previously described a novel molecular mechanism of Wnt pathway activation. We show that β-catenin is not only phosphorylated at 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.

Wnt pathway activating mechanism.

Wnt pathway activating mechanism. Schematic diagrams showing Wnt activating mechanism under normal (A) and cancer (B) condition (Click to view larger image)

We further show that APC truncation in CRC, 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 molecular mechanism of how APC mediates β-catenin ubiquitination in the destruction complex using CRC as a model.

In an independent research line, we are also interested in Wnt pathway activating mechanism in the non-APC mutated CRCs, often characterised by microsatellite-instability (MSI). This subtype, characterized by hypermutation due to genetic instability, might eventually obtain mutations in the Wnt pathway components such as β-catenin and Axin2.

Recent studies based on whole genome sequencing of large cohort of colorectal cancers, however, show that β-catenin and Axin2 mutations occur only in a small number of the non-APC mutated MSI cancers. We aim to further explore the Wnt-activating mechanism in MSI colon cancer using genome-wide association study.

Intestinal tissue engineering

Irreversible intestinal failure (IF) due to anatomical or functional loss is a devastating condition associated with significant morbidity and mortality. Although parenteral nutrition (PN) services have improved IF over the last decade, patients can suffer complications of PN. Such patients may be referred for intestinal transplantation, but many die before transplantation is available.

Recent advances in stem cell biology have opened up exciting avenues for intestinal tissue engineering (ITE) to provide alternatives to current treatments. Our goal is to engineer intestinal constructs using our intestinal organoids for regenerative medicine such as orthotopic transplantation and drug testing.

Selected publications

Li, VSW and Clevers, H (2012) In vitro expansion and transplantation of intestinal crypt stem cells Gastroenterology 143, 30-34

Li, VSW; Ng, SS; Boersema, PJ; Low, TY; Karthaus, WR; Gerlach, JP; Mohammed, S; Heck, AJR; Maurice, MM; Mahmoudi, T and Clevers, H (2012) Wnt signaling through inhibition of β-catenin degradation in an intact Axin1 complex Cell 149, 1245-1256

Mahmoudi, T; Li, VSW; Ng, SS; Taouatas, N; Vries, RGJ; Mohammed, S; Heck, AJ and Clevers, H (2009) The kinase TNIK is an essential activator of Wnt target genes EMBO Journal 28, 3329-3340

Kosinski, C; Li, VSW; Chan, ASY; Zhang, J; Ho, C; Tsui, WY; Chan, TL; Mifflin, RC; Powell, DW; Yuen, ST; Leung, SY and Chen, X (2007) Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors Proceedings of the National Academy of Sciences of the United States of Americacad Sci USA 104, 15418-15423

Vivian Li

vivian.li@crick.ac.uk
+44 (0)20 379 61502

  • Qualifications and history
  • 2008 PhD in Department of Pathology, the University of Hong Kong, Hong Kong
  • 2008 Postdoctoral Fellow, Hubrecht Institute, the Netherlands
  • 2013 Group Leader,Medical Research Council National Institute for Medical Research, London, UK
  • 2015 Group Leader, the Francis Crick Institute, London, UK