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Developmental and Stem Cell Biology

The stem cell and developmental biology program at CMB is engaged in a broad range of basic research aimed at understanding the molecular mechanisms underlying diverse aspects of embryonic development and tissue regeneration.

The long-term vision is that the delineation of key developmental strategies, and identification of molecules involved in these processes, will provide new paradigms in cellular transplantation and regenerative medicine.

Key areas of investigation are the identification and functional characterization of stem cell niches in developing tissues and adult organs. This research aims at characterizing molecules and signals involved in controlling the undifferentiated state and self-renewal capacity of stem cells, and to develop methods to direct the differentiation of stem cells into clinically relevant cell types. Extensive emphasis is also made on tissue differentiation and growth during embryogenesis, and deciphering mechanisms underlying the establishment cellular diversity in developing tissues and organs. Many of these questions are addressed in studies of the developing nervous system and in the mature brain.

A wide range of technical platforms and model organisms are applied to pursue relevant research topics. Basic genetic and molecular biology methodologies are combined with complementary bioinformatic and genome-wide approaches, allowing investigation global molecular changes in cells in various differentiation processes.

Infection and Cancer

The aim of the Infection and Cancer theme is to study how latent viral infections and chronic bacterial infections are associated with the development of cancer.

Common infectious diseases remain a major cause of morbidity and mortality worldwide. This is illustrated by the emergence of antibiotic resistant bacteria, and highly pathogenic viruses, such as HIV, SARS and new strains of influenza. In addition, infections contribute or are suspected to contribute to a surprisingly broad spectrum of malignancies.

We are focusing on the pathogen-host interaction at the cellular, tissue and organism levels, and are interested in understanding how this interaction alters processes involved in the regulation of genomic stability, cell cycle progression, cell death, and cellular and tissue re-modelling. The models used in our research are: the lymphotropic Epstein-Barr virus (EBV) and bacteria producing the cytolethal distending toxin (CDT), a bacterial genotoxin.

EBV is a DNA tumor virus that establishes latent infections in 90% of the human population world-wide. EBV has a dual life cycle characterized by the establishment of latency in B-lymphocytes and productive infection in epithelial cells. Latently infected B-cells express a restricted set of viral genes that promote a global rearrangement of the cellular environment leading to B-cell growth transformation and immortalization. The capacity of the latency viral gene to reprogram the control of cell proliferation and apoptosis and deregulate the maintenance of genome integrity is likely to underlie the association of EBV with a variety of malignancies, including virtually all cases of endemic Burkitt's lymphoma (BL) and nasopharyngeal carcinoma (NPC) and approximately half of Hodgkin's lymphomas (HL). Understanding the longstanding question of EBV oncogenesis in immuno-competent individuals is a crucial question.

Many pathogenic bacteria are highly pro-inflammatory and certain bacterial infections have been associated with increase cancer risk (e.g. Helicobacter pylori and gastric cancer). However, the exact mechanisms by which chronic bacterial infections contribute to carcinogenesis are poorly understood. Constitutive expression of TNF- alpha and activation of the transcription factor NF-kB seems to play a key role in the transition from chronic infection to malignancy. Several Gram-negative bacteria produce potentially DNA- damaging factors, including toxins, such as CDT, that may cause genetic instability and promote malignant transformation. In addition, some bacterial pattern molecules and virulence factors affect apoptosis and the control of cell cycle. Inflammation, induction of genetic instability, interference with cell cycle regulation and apoptosis could contribute to generate a carcinogenic tissue environment.

The groups in the Infection and Cancer theme focus on the following specific topics:

1. Viral and bacterial induced deregulation of cell cycle control
2. Viral and bacterial induced genomic instability
3. Interaction of infected cells with the surrounding micro-environment
4. Viral and bacterial interference with the ubiquitin proteasome system
5. Meta-genomic screening for identification of new viruses