The role of mast cells in tumor development and progression

• Applicant: Professorin Dr. Karin Hartmann
• Subject Area: Dermatology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 256860443

Mast cells are increased in many types of solid cancers and hematologic malignancies. The number of mast cells often correlates with tumor stage and prognosis, suggesting a tumor-promoting function of mast cells. However, in contrast to other immune cells of the tumor microenvironment, the precise role of mast cells in the biology of tumors remains largely unknown. This lack of knowledge is also due to the absence, until lately, of suitable mouse models for investigation of mast cell function. Our recently generated conditional mouse mutants which allow mast cell-specific gene inactivation provide us with the unique opportunity to unravel specific functions of mast cells in tumor biology.In our preliminary work, we established two new mouse models with selective deficiency of connective tissue mast cells. Using these models, we investigated the progression of subcutaneously injected tumors. We observed significantly decreased growth of tumors in mast cell-deficient mice. Moreover, mast cell deficiency was associated with decreased vessel density and, accordingly, tumor progression was delayed in mast cell-specific VEGF knockout mice. Analyzing the interaction between tumor cells and mast cells, we observed enhanced proliferation and cytokine production of tumor cells upon incubation with mast cell supernatant.In the present project, we will more specifically characterize the role of mast cells in tumor initiation, progression and invasion using different transgenic tumor models. Hypothesizing that mast cells can show plasticity exerting pro- and anti-tumorigenic functions depending on tumor stage, we plan to define mechanisms that determine polarization of mast cells within the tumor microenvironment using flow cytometry, mRNA transcriptome analysis and a transgenic approach. We will further define the role of mast cells in tumor angiogenesis. We will explore the differential contributions of mast cell-derived and tumor cell-derived VEGF. Additionally, we will investigate the interaction of mast cells with other immune cells of the tumor stroma analyzing the distribution of immune cells in mast cell-deficient mice and assessing tumor progression in mast cell-specific knockouts of surface receptors, which interact with other immune cells.

• DFG Programme: Research Grants