Dmitry Bulavin obtained his MD in 1994 and his PhD in 1996 from the Medical Academy, St. Petersburg, Russia. He did his postdoctoral work at the National Cancer Institute (Bethesda, USA) where he found that mammalian p38 kinase plays an important role in a negative regulation of cell cycle progression and transformation. He joined IMCB in 2004 as an Assistant Professor and a principal investigator.

Understanding the mechanisms underlying the behavior of stem cells and their implications in tumorigenesis and ageing are of great importance and paramount to the design of more effective treatments for human diseases. In many, if not all instances, in vivo interrogation of stem cells is intimately linked to the lineage tracing protocols, which, in turn, depends on the identification of appropriate stem cell markers. We recently identified several such markers, including Wip1 phosphatase, which is a key stem cell regulator in the mouse brain and small intestine.

Wip1 phosphatase is a member of PP2C family of phosphatases and is highly abundant in neural progenitors and intestinal stem cells. Functionally, Wip1 is a negative regulator of p38 MAPK and ATM-dependent signaling pathways, both of which play critical roles in regulating tumorigenesis and ageing. Wip1 deficiency results in tumor resistance in mice, which in turn, is linked to a higher sensitivity to p53-dependent apoptosis. Activation of oncogenes in stem cells, an early event in tumorigenesis, results in conversion of stem cells into tumor-initiating/cancer stem cells. In contrast, if Wip1 is deleted or inactivated during this conversion process, p53 undergoes hyperactivation and, consequently, a newly formed cancer stem cell is eliminated via apoptosis. This mechanism is critical in cancer prevention and could provide the basis for the development of therapies for patients with cancer-prone mutations such as APC and BRCA1/BRCA2.
    
 Using our recently developed tools and acquired knowledge, we emphasize the role of stem cells in regulation of tumorigenesis and ageing with particular interest in stress signaling kinases p38 MAPK and ATM and phosphatases, Wip1 and PP2A.

The role of stem cells as the origin of cancer has never been proven using defined genetic approaches. One difficulty is that it is virtually impossible to dissect whether cancer originates in a stem cell or an early progenitor. Using a newly develop genetic system based on the spatial and transient regulation of expression of Cre-recombinase, we will attempt to trace the stem cell origin of cancer. The model of choice for this set of experiments is the APCMin-driven intestinal polyposis. Once the system is developed, it will be used in the context of different tumor-prone and tumor-resistant mouse strains to understand if deregulation of tumor suppressors or oncogenes modifies the cancer origin.

The ability to trace stem cells using specific markers and surface antigens, in particular, will help to elucidate the role of cancer stem cells in cancer initiation, maintenance and reoccurrence. Information about such markers could be obtained from the analysis of gene expression profiles of purified populations of stem cells. In this respect, different reporter mouse strains that label stem cells will be used to isolate stem cells from different organs. Once such markers are identified, our investigation will be extended to stem cell behavior during the course of tumorigenesis in vivo.

One emerging concept is that cancer represents a backward step in differentiation. A small population of cancer cells, called cancer stem cells, is though to acquire stem cell-like features and critical to maintain the cancer. The ability to generate such cancer stem cells is linked to the concept of the stem cell niche, the environment that is required for the maintenance of stem cells. Learning how to control such an environment would offer more efficient control of cancer. We are planning to approach this problem by identifying the markers of stemness and our further interrogation of the stem cell niche. In this respect, the role of p38 MAPK is of particular interest with the use of several p38 MAPK knock-in mouse strains recently generated in the lab. 

In parallel with our efforts to understand the role of stem cells in tumorigenesis, we will investigate the molecular basis of ageing. The process of organismal ageing is characterized by the functional decline and diminished capacity of different tissues to respond to injury or stress. As stem cells are involved in homeostasis as well as the regeneration and repair of many tissues, the question naturally arises as to whether ageing tissue is characterized by a decline in functional competence of resident adult stem cells. This question will be addressed using several mouse strains that show a substantial increase in stem cell apoptosis and depletion of stem cell pool with age. In parallel, we will attempt to lower the rate of spontaneous apoptosis of stem cells to address the question of whether protecting stem cells from apoptosis and thus from premature depletion will contribute to longevity. These questions will be approached first by the use of mouse strains with different levels of expression of Wip1 and p38 MAPK. 
     
Declining tissue homeostasis or repair could arise from age-related changes in the numbers or properties of stem cells, in the local environment or niche, in the systemic changes of the organism, or in any combination of all of these factors. Thus, even in the absence of significant ageing of stem cells themselves, stem cell activity could show a marked age-related decline due to attenuated signaling within the local and systemic environment. Our preliminary data strongly support the role of stress-induced signaling pathways in regulation of tissue ageing through modulation of transcription of several ageing-related genes. For example, we recently generated mouse strains with modulated age-related expression of Ink4a, a gene responsible for age-related decline in functional competence of different tissues. These strains will be further used to understand the molecular pathways responsible for activation of Ink4a with age, its role in organismal ageing and the role of microenvironment in the functional activity of stem cells.