Francis Crick Institute
Crick Cancer Clinical Research Fellow Programme
Three-Year Clinical Research Training Fellowships 2016
Names of project supervisors:
Crick supervisor: Vivian Li
CRUK Centre/University supervisor: Marco Novelli (UCL)
Title of research project:
Targeting Wnt signalling pathway in human colorectal cancer using live
organoid biobank
Description of the research project :
The evolutionary conserved Wnt signalling pathway plays essential roles during embryonic
development and tissue homeostasis. Besides its crucial role in tissue homeostasis, Wnt
signalling has also been implicated in a variety of cancers and other diseases. Loss of the
Wnt pathway negative regulator APC is the hallmark of human colorectal cancers (CRC).
Despite many exciting preclinical studies targeting the Wnt signalling pathway in cancers
and other disease models, only a limited number of agents have recently entered clinical
trials (1). To develop more effective Wnt inhibitors, it is important to answer outstanding
questions relating to the mechanisms by which the Wnt pathway functions.
We have previously redefined the Wnt activating mechanism under normal physiological
condition (2). Further study in the host laboratory has identified the deubiquitinating
enzyme USP7 as an essential player to sustain pathological Wnt activation in APC-mutant
CRCs (unpublished data). Preliminary data show that inactivation of USP7 can suppress
Wnt activation and growth of APC-mutated human CRCs, suggesting it as an attractive
therapeutic target. To date, most preclinical studies rely largely on non-physiological
cancer cell lines or complicated and time-consuming patient-derived xenografts. Recent
development of cancer organoids allows us to establish efficient and long-term culture of
primary human CRC tissues, which provide attractive physiological disease models for
high-throughput drug screening (3-5).
The aim of the project is to establish a human colorectal cancer organoid biobank and
perform drug screening targeting the Wnt signalling pathway. The host laboratory at the
Crick has expertise in culturing 3D murine and human intestinal organoids derived from
both normal and tumour tissues. The lab is also experienced in characterising Wnt
signalling pathway regulation in intestinal tissue homeostasis and tumourigenesis. The
secondary supervisor at UCL is a consultant histopathologist specialised in
gastrointestinal pathology. Together, we will be able to obtain primary human CRC
tissues for the establishment of the live tumour organoid biobank to perform Wnt
inhibitor screening. We aim to specifically screen for the drug efficacy of the USP7
inhibitors in our human CRC organoids, which has already been tested in murine tumour
organoids. We will also screen for other recently reported Wnt inhibitors in our human
primary CRC organoids and compare the drug efficiency with those reported pre-clinical
studies in cancer cell lines.
The candidate will learn to establish 3D-organoid biobank derived from primary human
normal and cancerous intestine. Other techniques include (but are not limited to) clinical
record keeping, histopathology, organoid drug screening, biochemistry and confocal
imaging etc. Candidate with experience on tissue culture or biochemistry technique
would be advantageous.
References:
1. Novellasdemunt L, Antas P, Li VS. Targeting Wnt signaling in colorectal cancer. Am J
Physiol Cell Physiol. 2015 (in press)
2. Li VS, Ng SS, Boersema PJ, Lo TY, Karthaus WR, Gerlach JP, Mohammed S, Heck AJ,
Maurice MM, Mahmoudi T and Clevers H. Wnt signaling inhibits proteasomal β-catenin
degradation within a compositionally intact Axin1 complex. Cell. 2012 Jun
8;149(6):1245-56.
3. Sato T, Stange DE, Ferrante M, Vries RG, Van Es JH, Van den Brink S, Van Houdt WJ,
Pronk A, Van Gorp J, Siersema PD, Clevers H. Long-term expansion of epithelial
organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium.
Gastroenterology. 2011 Nov;141(5):1762-72.
4. Li VS and Clevers H. In Vitro Expansion and Transplantation of Intestinal Crypt Stem
Cells. Gastroenterology. 2012 Jul;143(1):30-4.
5. van de Wetering M, Francies HE, Francis JM, Bounova G, Iorio F, Pronk A, van Houdt
W, van Gorp J, Taylor-Weiner A, Kester L, McLaren-Douglas A, Blokker J, Jaksani S,
Bartfeld S, Volckman R, van Sluis P, Li VS, Seepo S, Pedamallu CS, Cibulskis K, Carter
SL, McKenna A, Lawrence MS, Lichtenstein L, Stewart D, Koster J, Versteeg R, van
Oudenaarden A, Saez-Rodriguez J, Vries RG, Getz G, Wessels L, Stratton MR,
McDermott U, Meyerson M, Garnett MJ, Clevers H. Prospective derivation of a “Living
Organoid Biobank” of colorectal cancer patients. Cell. 2015 May 7;161(4):933-45.
Summarise the medical/clinical component of the research, as well as the relevance
to the Crick Cancer CRF programme:
According to the World Health Organizations’ GLOBOCAN 2012, colorectal cancer (CRC) is
the third most common cancer in men and the second in women. Aberrant Wnt signalling
has been associated with many cancers including CRC, and is therefore an attractive
target for therapeutic intervention. Thus far, no approved drug targeting Wnt signalling
is available in the clinic despite the substantial effort in the past two decades. One
major challenge of targeting Wnt pathway is that it has a crucial role in normal tissue
homeostasis. Many high-turnover tissues such as gastrointestinal epithelium and hair
follicles require Wnt signalling for stem cell maintenance and tissue regeneration.
Interference with this pathway will target not only Wnt-activated cancer cells but also
the normal stem cell populations of those Wnt-dependent tissues, resulting in significant
toxicity. We have recently identified USP7 as a novel tumour-specific target for APCmutated CRCs to inhibit Wnt pathway without significant toxicity, providing an excellent
target for treatment of APC-mutated CRCs (>85% of total CRCs).
The current interdisciplinary project involves the establishment of primary CRC organoid
biobank and drug screening, which provides an excellent training opportunity for
candidate to perform cutting-edge research at the Crick in collaboration with the
clinicians at UCL.
Project supervisors’ contact details:
Crick supervisor:
Name: Vivian Li
Telephone: 020 8816 2132
Email: Vivian.Li@crick.ac.uk
CRUK Centre / University supervisor:
Name: Marco Novelli
Telephone: 020 7679 6657
Email: m.novelli@ucl.ac.uk