The Guezguez lab was launched recently as part of the DKTK consortium in Cancer Immunotherapy and hosted by the Department of Hematology, Oncology, and Pneumology at the University Medical Center of the Johannes Gutenberg-University of Mainz.
Our research program is focused on dissecting how cancer hijacks stem cell processes and immune properties in normal and malignant hematopoiesis (myelodysplasia and myeloid leukemia). Of major interest is the signalling crosstalk between stromal cells, cancer stem cells and immune cells. To address this, we take a multidisciplinary approach grounded in studies using primary human cells, 3D cultures and leukemia mouse models and capitalize on functional screening of epigenetic/metabolic modulators and developing novel imaging techniques.
Using this approach, we aim to identify the molecular regulatory processes that upon dysregulation lead to cancer transformation/relapse, immune escape and therapy resistance. In doing so, we hope to identify critical therapeutic targets that lead toward translational development of novel cellular therapies for cancer treatment and regenerative medicine.
Myelodysplasia and leukemic transformation
Myelodysplastic syndromes (MDSs) are hematologic disorders that represent an intermediate disease stage before progression to lethal acute myeloid leukemia (AML). AML is one of the most aggressive cancers of the hematopoietic system with a median survival as low as one year (Cancer Facts & Figures 2017; Leukemia and Lymphoma Society). The risk of MDS increases with age (median age at diagnosis 70 years) and disease-associated morbidity impacts quality of life and represents a burden on the health care system. MDS symptoms include anemia, cytopenia (low level of blood cells) and ineffective hematopoiesis. If left untreated, death can occur as a result of infections and bone marrow failure. Thus far, few treatments can actually alter the natural pathogenesis of this disease and allogeneic stem-cell transplantation remains the only curative therapy, especially for high-risk cases. The lack of other therapeutic options underscores the urgent need to develop new therapies. We recently developed a surrogate mouse model that can faithfully recapitulate the MDS/AML human disease (Guezguez et al., Cancer Cell 2016). This model can be used as a potential tool to decipher the oncogenic role of signaling pathways in the emergence of the disease and pinpoint potential therapeutic targets.
Cancer Stem Cells and tumor microenvironment
Recent advances in gene sequencing studies demonstrated that MDS is a clonal malignancy affecting a rare cell subset called hematopoietic stem cells (HSC) which reside in the bone marrow microenvironment (BM). HSC are responsible for the daily production of functional immune and blood cells throughout life (differentiation) while maintaining the capacity to make exact copies of themselves (self-renewal). The balance between HSC self-renewal and differentiation is tightly controlled by a number of mechanisms that include transcription factors, signal transduction pathways, and BM factors such Notch pathway that is modulated by the osteoblastic/mesenchymal stromal populations (Guezguez et al., Cell Stem Cell 2013). In addition, recent studies provided overwhelming evidence suggesting that epigenetic modifications, such as DNA methylation, act in concert with these transcriptional factors to ensure hematopoietic homeostasis. Deregulation of epigenetic mechanisms that control this balance can cause aberrant HSC function and lead to transformation into cancer stem cells (CSC). This transformation, supported by dysfunctional stromal BM cells, contributes to tumor onset, expansion, therapy resistance and recurrence. However, it is still unclear which specific epigenetic alterations and/or cumulative genetic mutations affect the HSCs directly and favor this transformation to MDS/AML. As such, the study of CSC from MDS/AML mouse models can provide insight into the mechanisms of neoplastic evolution and allow us to pinpoint new therapeutic targets.