A cancer membrane nanoparticle toolbox to study and treat leukemia
In Acute Myeloid Leukemia (AML), recurrence and chemoresistance occurs partially due to the strong interactions Leukemic Stem Cells (LSCs) have with the bone marrow where they hide. It is these native interactions that we investigated by using cell membrane nanoparticles as a tool to treat and study leukemia.
First, we developed a reproducible, robust, detergent free and scalable method for the extraction and purification of plasma membrane from bone marrow and leukemia cells. Leukemia membrane liposomes were more rigid than liposomes, implicating incorporation of membrane material, and displayed enhanced association with bone marrow cells and leukemia cells but not in breast cancer cells, highlighting cell-specificity. Contrarily, bone marrow nanoparticles were soft and did not show enhanced interaction with either target cells.
Upon increasing rigidity of the bone marrow nanoparticles by depositing the membrane and lipids on a solid core, enhanced interaction was observed. Our hypothesis is that the proteins present on the nanoparticles are now able to effectively engage the receptors on the target cells due to the increased rigidity. These findings were confirmed in patient material, where more rigid stromal membrane nanoparticles showed enhanced interaction and uptake in LSCs.
Since we established cell membrane nanoparticles that display specific interactions, we used them in a proteomic screening to investigate native interactions between the cells of origin. By utilizing the particle properties, cell membrane nanoparticles and their membrane proteins in the screening were analyzed, identifying novel potential mediators of cell-cell adhesion in the bone marrow niche.