Project 461679

Medulloblastoma (MB) is the most prevalent malignant brain cancer in children. Some forms are highly metastatic, and infiltrate the brain and spinal cord, leading to severe morbidity. Molecular characterization of MB tumors has identified defects in several different genes. Interestingly, at least one of these genetic changes occurs in brain cells that likely don't represent the tumor forming cell, but rather, contribute to tumor progression by providing an environment conducive for tumor cell survival and growth. These non-tumour cells are components of the tumour microenvironment and they exhibit a variety of functions that influence tumour initiation, growth and progression. The brain stroma is a type of non-tumour cell that is thought to contribute to tumor progression and metastasis, and contains, in addition to other cell types, blood vessel-associated mesenchymal progenitors (MPs). MPs are a type of adult stem/progenitor cell, that are found to varying extents throughout the body, and play critical roles in tissue development, growth, homeostasis and regeneration. MP participation in brain cancers has been challenging to study because good genetic tools in which to study their behaviour and function in tumors of the central nervous system are lacking. We have generated unique mouse models that enable us to identify, track and experimentally manipulate MPs in the brain. This application will focus on studying how these tumor-associated cells contribute to and promote MB tumor formation and to determine if they represent a suitable therapeutic target for the treatment of brain cancers such as MB. These non-tumor MPs represent a universal TME component within all solid tumors and thus, therapeutic strategies emanating from this research would be applicable to the treatment of a wide range of solid tumours.