UC San Diego

Macrophages are innate immune cells that play key roles in infection, immunity and cancer. Understanding the mechanisms that control macrophage contributions to cancer can help to develop strategies to improve cancer therapy. Oncogenic mutations allow cancer cells to take up nutrients through a process called macropinocytosis or “cell-drinking”, which promotes cancer cell survival and proliferation. The role of macropinocytosis has been studied in various cancers but has been less well explored in macrophages. Macropinocytosis in macrophages may help these cells to survive in the harsh tumor microenvironment. Thus, one of the goals of this project is to investigate macrophage macropinocytosis by studying the uptake of Tetramethyl rhodamine (TMR-dextran) in macrophages. My hypothesis is that PI3Kgamma plays a role in promoting macropinocytosis in macrophages. Through macropinocytosis assays using TMR-dextran, we found that PI3Kgamma inhibition successfully suppressed macropinocytosis in iWT macrophages. To further study macrophages, we tested the effect of 3G8, a small molecular drug that inhibits FLT3, CKIT and CSF1R, on mitochondrial function. We had found that 3G8 can also stimulates release of mitochondrial ROS. My hypothesis is that 3G8 activates the mitochondrial permeability transition pore (thereby releasing ROS and impacting cell signaling). Through mitochondrial permeability transition pore activity (mPTP) assays, we observed that 3G8 induced opening of the mPTP in macrophages and tumor cells. Understanding the mechanisms by which these inhibitors function in macrophages could help with the development of anti-cancer therapeutics and thus reduce the effects of cancer.