Research Programmes
Oncology
Colorectal cancer laboratory II
Elena Sancho
Principal Investigator
Institute for Research in Biomedicine
Office Tel : + 34 93 403 90 07
Lab Tel : + 34 93 403 49 82
e-mail : elena.sancho
irbbarcelona.org
Background
Only last year, more than half a million people worldwide died of Colorectal Cancer (CRC), making CRC the second cause of death by cancer. Most sporadic colorectal cancers arise from adenomas that initially are benign and occur frequently: approximately 50% of the Western population develops an adenoma by the age of 70. Early adenomas are a consequence of mutational activation of the Wnt signalling pathway in the intestinal epithelium. Our results indicate that these mutations impose a progenitor phenotype onto mutated cells that leads to the constitutive production of proliferative cells in the intestinal epithelium. Early colorectal lesions composed of proliferative progenitors are prone to the accumulation of alterations in key oncogenes and tumour suppressor genes that eventually lead to progression though the different stages of malignancy.
Research Interests
We study the initiation and progression of CRC through a multidisciplinary approach that includes the use of cell and animal models, as well as gene expression profiling of tumour samples. Our goal is to examine the molecular mechanisms that govern the initiation and progression of this disease with the aim of identifying molecules and pathways susceptible to being targeted by the drug industry.
Research Lines
1.- 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).
2.- 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.
Funding
This group receives financial support from the following sources:
- Ministerio de Educación y Ciencia (MEC- Spanish Ministry of Science and Education)
- Generalitat de Catalunya (Government of Catalonia)
