Johanna Joyce, PhD

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.

Figure 1 Interactions between tumor cells and their microenvironment are critical at all stages of tumor development and metastasis. Many of the non-cancerous cells that comprise the tumor microenvironment originate from the bone marrow, including tumor-associated macrophages.
Model by Hao-Wei Wang, Joyce lab.

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.

Figure 2 Cathepsin proteases produced by bone marrow-derived macrophages enhance tumor growth, invasion and angiogenesis. This immunofluorescent image shows bone-marrow derived cells (BMDCs, green) in close association with the tumor vasculature as visualized by CD31 staining (red); nuclei were stained with DAPI (blue). The BMDCs are recruited to and infiltrate the tumor mass, where they differentiate into macrophages. Upon exposure to tumor-derived IL-4, macrophages induce cathepsin protease activity, which in turn can regulate a number of tumorigenic processes including blood vessel development.
Image provided by Leny Gocheva, Joyce lab. For details, see Gocheva, Wang et al, Genes Dev 2010.

Figure 3 In response to chemotherapy, breast tumor-associated macrophages (TAMs) secrete cathepsin proteases that decrease chemosenstivity. Shown here is an immunofluorescence analysis of mouse mammary tumor tissue using antibodies directed against macrophages (white). Tumor cells are labeled in green, DAPI (blue) is used to visualize the cell nuclei, and a cathepsin activity-based probe is in red. Taxol treatment results in an increase in cathepsin-positive macrophages in the tumor. These macrophages are able to protect tumor cells from chemotherapy-induced cell death in a cathepsin-dependent manner, and represent a novel mechanism of acquired resistance.
Image provided by Oakley Olson, Joyce lab. For details, see Shree, Olson et al, Genes Dev 2011.