Cancer cells do not exist in isolation but rather within a complex milieu of normal cells, secreted proteins, physiological small molecules and blood vessels which comprise the tumor microenvironment. Recent advances have indicated that the tumor microenvironment is critically important for cancer initiation, progression, metastasis and drug resistance, opening up opportunities for therapeutic intervention. We have focused on three systems modeling tumor microenvironment interactions models to identify small-molecule probes that perturb them:
Cancer stem cells. The malignant counterparts of normal hematopoietic stem cells (HSCs), called leukemic stem cells (LSCs), reside in a specialized ‘niche’ within the bone marrow where they interact with osteoblasts and mesenchymal stem cells (MSCs). These leukemic stem cells have the unique ability to initiate leukemia, self-renew and differentiate, and are thought to be the root cause of relapse in patients treated with traditional cancer drugs. To target these cells, we have used primary LSCs and MSCs to reconstruct the microenvironment ex vivo. In parallel, we use primary HSCs with MSCs to represent normal hematopoiesis. The goal of this highly collaborative project is to use high-throughput image-based screening to identify novel anti-leukemic or pro-normal stem cell small molecules in the context of their bone marrow microenvironment.
Multiple myeloma. Multiple myeloma (MM) is a malignancy of plasma cells that, like leukemia, arises in the bone marrow. Primary MM cells have an obligate dependence on interactions with bone marrow MSCs to maintain viability. These interactions also lead to resistance to traditional anti-myeloma drugs such as dexamethasone. We have undertaken screening efforts to identify small-molecule inhibitors of microenvironment-dependent MM cells.
Breast cancer metastasis. There are no definite genetic alterations associated with the acquisition of metastatic properties in breast cancer cells. Recent advances have shown that bone marrow derived MSCs home to the sites of breast cancer growth and promote metastasis of the cancer cells. We have undertaken systematic efforts to uncover the mechanisms of MSC-promoted breast cancer metastasis and will use small molecules to target those mechanisms.