Cancers develop in complex tissue environments, which they depend upon for sustained growth, invasion and metastasis. The tumor microenvironment comprises innate and adaptive immune cells, fibroblasts, extracellular matrix, and blood and lymphatic vascular networks, which collectively have critical modulatory functions in tumor development and metastasis (Figure 1).
Our lab is interested in the critical influence that non-cancerous stromal cells can have on tumor progression and response to therapy. We investigate both positive and negative signals provided by the normal tissue stroma to the cancer cells, and how normal cells can be modified by the cancer cells to produce a variety of factors that enhance tumor malignancy. One of the critical regulatory cell types in the microenvironment are tumor-associated macrophages (TAMs), which have a potent ability to promote tumor progression.
We have concentrated on two main areas: unraveling the reciprocal communication between TAMs and cancer cells in the tumor microenvironment, and investigating the mechanisms by which TAM-derived proteases promote tumor development and impair therapeutic response (Figure 2). We have investigated several distinct tumor microenvironments, including pancreatic and breast cancers, gliomas and brain metastases, cognizant of important differences between organ sites in the body.
A major current focus of the lab is to understand the mechanisms by which stromal cells regulate the later stages of tumor progression, namely invasion and metastasis. Moreover, emerging evidence indicates that stromal cells are mobilized and activated following anti-cancer therapy, and apparently contribute to a lack of response/ resistance to treatment. Tumors that recover from harsh cytotoxic assaults must engage programs of matrix remodeling, neo-angiogenesis, and cell repopulation, all processes that typically involve stromal cells. Our lab is identifying the mechanisms underlying the contribution of the stromal microenvironment to therapeutic resistance, an important area of research that remains largely unexplored (Figure 3). We employ a range of complementary approaches to address these questions including mouse models of cancer, 3D co-culture systems, and analysis of patient samples in collaboration with our clinical colleagues. Our ultimate goal is to apply this knowledge to the clinic and develop targeted therapies that disrupt essential tumor-stromal interactions.