Pre-doctoral Fellowship Grant Awarded to Andrea Cruz

It is widely recognized that the tumor cells’ (“the seed”) surrounding ecosystem, known as the tumor microenvironment (“the soil”), plays an active role in supporting tumor survival and promotion, immune evasion, and chemoresistance. The tumor microenvironment (TME) is comprised of tumor cells, a myriad of normal and immune cells, extracellular matrix, blood vessels and many other factors, which are all constantly cross-talking and influencing each other. Within the TME, tumor cells secrete an array of chemical signals that hijack normal tissue support systems and avoid destruction from the immune system.

Within the DMG-H3K27a (formerly known as DIPG) tumor mass, the dominant non-tumor cell population are glioma-associated microglia and macrophages. In healthy brain and spinal cord tissue, specialized immune cells known as microglia and macrophages play a key role in innate immunity by fighting infections, clearing cellular debris, and eliminating tumor cells. However, in the DMG-H3K27a TME, tumor cells co-opt microglia and macrophages into secreting growth factors that promote tumor growth and progression instead. The identity of the microglial-derived growth factors and their effect on tumor biology is not well characterized. In our preliminary studies, we have discovered and identified microglial-derived growth factors that DMG-H3K27a tumor cells are dependent on, which represents new avenues for developing targeted therapies.

The primary objectives of this research are to 1) investigate the biological consequences of microglial secretion of growth factors and its effect on DMG-H3K27a tumor growth and progression in vitro and 2) evaluate the therapeutic potential of targeting the cell-cell communication between microglial cells and tumor cells by using blood brain barrier penetrant, clinically relevant drugs, and a neutralizing antibody we have developed in vivo. Ultimately, these findings provide further insights on DMG-H3K27a biology and inform future therapy paradigms.