OncologyColorectal cancer laboratory
Unraveling Cancer Stem Cells and the Origins of Metastasis
ICREA Research Professor
ERC Advanced Grant
Colorectal Cancer (CRC) is one of the leading causes of death by cancer worldwide. Most colorectal tumors develop as benign lesions but a small proportion progress to more malignant stages when the appropriate alterations in oncogenes and tumour suppressor genes occur. The final and deadliest step in colorectal cancer progression is the metastatic dissemination of colorectal cancer cells to other organs, mainly the liver.
Our lab studies the initiation of CRC and its progression from the early stages to the formation of aggressive tumors. We develop and examine cell and animal models that mimic this devastating disease. The ultimate goal is to obtain information that allows us to design new therapeutic and diagnostic tools.
1) Intestinal stem cells and CRC stem cells
Our studies address the identification, isolation and profiling of normal crypt stem cells and their malignant counterparts. We aim to identify the relationship between cell renewal in the intestinal epithelium and the initiation and progression of CRC.
2) EphB/ephrinB receptors in CRC
We recently demonstrated that the beta-catenin/Tcf target genes EphB2 and EphB3, two receptors of ephrinB ligands, suppress CRC progression beyond the early stages of tumor development. Most CRC silence the expression of EphB receptors around the adenoma-carcinoma transition, despite constitutive Wnt signalling. We are currently studying how EphB activity blocks tumor malignization as well as the mechanism of EphB down-regulation in advanced CRC.
Early Colorectal Cancer lesions (dashed line) showing nuclear beta-catenin accumulation and expression of EphB2
3) The colonization of the liver by CRC cells
Liver metastasis is the main cause of death by colorectal cancer, yet the molecular mechanisms responsible for liver colonization by colorectal cancer cells remain largely unknown. We aim to identify the genes required by CRC cells to colonize the liver, with the focus on developing new therapeutic approaches to tackle the spread of CRC.
4) Molecular mechanisms that govern stem cell specification in normal epithelium and in CRC initiation
The intestinal epithelium is a prime example of cell renewal in adult tissues. The proliferative compartment of the intestinal epithelium is structured in millions of invaginations known as crypts of Lieberkühn. Each of these structures is a developmental unit that contributes to the complete renewal of the epithelium every few days throughout adulthood. Cell renewal in the intestinal epithelium is maintained by a small group of intestinal stem cells that reside at the bottom of each crypt. These stem cells slowly but continuously duplicate, giving rise to a transient population of progenitor cells that rapidly divide whilst migrating towards the intestinal lumen. In the mid-crypt region these cells stop dividing and differentiate. After 3-5 days, they are shed to the lumen and replaced by fresh descendants from the bottom of the crypts. Wnt signals are required for the maintenance of stem cells but also for the initiation of CRC. We study the similarities and differences in the molecular mechanisms responsible for the maintenance of stem cells and mutant stem cells in response to Wnt signals through the generation of animal models that mimic the initiation of the disease. These studies aim to identify molecular targets that may be used during early stages of the disease, and, in particular, in patients suffering from familial adenomatous polyposis (FAP).
5) Contribution of mutations in other signalling pathways to CRC progression
As CRC progresses, mutant cells accumulate alterations in other signalling pathways that modulate the initial progenitor phenotype imposed by mutations in Wnt signalling. Our research currently focuses on the contribution of TGF beta signalling to carcinogenesis through a multidisciplinary approach that includes gene expression profiling of tumour samples and the use of cell culture models and animal models in which TGF beta signalling is selectively induced or abolished in the intestinal tract.
Speaker: Prof. René H. Medema,
Netherlands Cancer Institute, Amsterdam, The Netherlands
Speaker: Dr. Laura Spagnolo,
University of Edinburgh, School of Biological Sciences, Institute of Structural Molecular Biology, UK
Speaker: Dr. Israel Sanchez,
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, UK
Speaker: Riccardo Fodde,
PhD, Dept. of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
This group receives financial support from the following sources:
- Ministerio de Educación y Ciencia (Spanish Ministry of Science and Education)
- European Commission (FP6)
- Generalitat de Catalunya (DURSI) (Government of Catalonia)