Targeting microenvironment-induced TGFB signaling to overcome drug resistance in acute lymphoblastic leukemia
The goal of this project is to understand how the interaction of B-cell acute lymphoblastic leukemia (ALL) cells with the tumor microenvironment affects response to therapeutic drugs, and to explore how we can overcome this drug resistance. Relapsed ALL is second leading cause of childhood cancer death and remains problematic. Only 50% of children are cured when they enter remission after first relapse. Most studies of relapse have focused on features inside the tumor, but not tumor-microenvironment interactions of leukemic cells, which are important to impair drug response in other cancers. Studies of myeloid leukemia cells showed that bone marrow microenvironment provides to the leukemia cells important signals that support proliferation. However, there have been few reports investigating ALL-microenvironment interactions. Our preliminary data show that ALL-microenvironment interactions are dynamic and result in drug resistance. Cells become more adhesive and express genes known to cause epithelial-mesenchymal transition, which is known to drive invasion and drug resistance in solid tumors.
This project will examine the role of tumor microenvironment in drug resistance of ALL. To understand the mechanism of ALL-microenvironment interaction, we will use single cell genomic and proteomic tools to characterize the molecules and signaling pathways that are mis-regulated when ALL cells interact with the microenvironment. This will lead to the development of novel therapies that reverse adherence and increase sensitivity to cytotoxic drugs. Overall this study will provide a rationale to guide the development of clinical trials testing new agents to overcome resistance and improve overall survival of this disease.