Our research group has the main aim of deciphering the molecule mechanisms regulating the generation and maintenance of stem cells, and their differentiation until they are mature and functional cells. Within this general aim, we are particularly interested in studying the signalling pathways that intervene, in one way or another, in controlling tumour processes. For this reason we created the Research Group on Stem Cells and Cancer, which brings together two research teams, lead by doctors Anna Bigas and Lluís Espinosa. This group was created over a decade ago and, through joining efforts we have managed to reach scientific goals of the highest level in the field of biomedical sciences, besides contributing to training new researchers, some of whom are currently working in several national and international centres.
In recent years we have developed several experimental methods to deal with specific biomedical problems on all levels. In fact, the experimental approach followed by our group ranges from biochemical research in a lab and animal model analyses reproducing pathologies that are of interest and allow us to confirm our molecular findings, to studies on the possible therapeutic application of our findings through analysing patient samples. In this sense we have put a great deal of effort into understanding the mechanisms regulating some tumour processes such as leukaemia or colon cancer.
Among the biochemical mechanisms that regulate the tumour progressions, such as stem cell homeostasis, it is relevant to point out those that are regulated by the Notch, Wnt and NF?B signalling pathways. Studying these pathways in haematopoietic, intestinal and skin tissues has also lead us to identify interactions between several of these pathways, which has proved essential to understanding tissue homeostasis.
At present, the group lead by Dr. Anna Bigas is working on several projects looking at several aspects of the Notch function in normal haematopoietic stem cells, as well as in leukaemia initiating cells. The work directed by Dr. Lluís Espinosa mainly focuses on studying how NFKB and Notch are co-regulated in several normal and tumour processes, and how this crossed regulation contributes to the tumour genesis and progression.
Generation and maintenance of haematopoietic and intestinal stem cells
For this project we are using different strands of mutant mice for the Notch pathway with the aim of studying their role in generating and maintaining haematopoietic stem cells both in embryos and in adult mice. With this strategy we have shown that the Notch and Wnt/beta-catenin are both essential to generate haematopoietic stem cells. In parallel to this, we also observed and showed how these signalling pathways act together to maintain intestinal cells.
Generation and self-renewal of tumour or leukaemia initiating cells
We aim at determining what signalling pathways are relevant for the generation and maintenance of leukaemia initiating cells (LIC) and tumour stem cells. To deal with this aim we are developing several experimental models, both in vitro and in vivo. We are also using mass sequencing analysis to determine those changes in the genetic expression (RNA-seq, exon sequencing) in controlling transcriptional regulation (Chip-Seq) and in the specificity of protein complexes (mass spectrometry) that may prove useful in defining these populations from a molecule and functional point of view. Our studies show that Notch, Wnt or NFKB pathways are activated mutually or sequentially in different tumour processes. Also, we detected that some of the elements in these pathways are physically associated, which is relevant at a functional level.
New functions of the NFkB pathway in oncogenesis or leukemogenesis
In recent years we have proven that different elements regulating the NFKB pathway have alternative functions regulating gene transcription. For example, our works have been pioneering in identifying IKKa and IkBa as proteins that bind to the specific gene chromatin that are not the typical targets of NFKB, and intervene in transcriptional regulation. We have also proven that these new nuclear functions of IKKa and IkBa are especially relevant in tumour processes such as colon and rectal cancer and in squamous skin carcinoma. Further studying the role of these proteins and their relevance for tumour control processes is one of the main aims of the group.