Johanna A. Joyce, PhD

2009-2010 BCRF Project
Metastasis is a multi-stage process that requires cancer cells to escape from the primary tumor, survive in the circulation, colonize distant sites and grow. Each of these processes involves rate-limiting steps that are influenced by non-malignant cells of the tumor microenvironment. Many of these cells are derived from the bone marrow and are recruited by cancer cells to enhance their survival, growth, invasion and dissemination.

For example, bone marrow-derived cells (BMDCs), including macrophages, neutrophils, and mast cells have been shown to contribute to tumor angiogenesis and growth. However, the mechanisms by which BMDCs regulate the later stages of tumor progression, namely invasion and metastasis, are still poorly understood, and will be a major focus of this project. Moreover, emerging evidence indicates that BMDCs are mobilized 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, neoangiogenesis, and cell repopulation, all processes that typically involve stromal cells and BMDCs.

Dr. Joyce aims to identify the mechanisms underlying the contribution of the host microenvironment to therapeutic resistance, an important area of research that remains largely unexplored.

Mid-Year Progress Report:
Cancers develop in a complex microenvironment, in which tumor cells recruit stromal cells from the surrounding tissue and the bone marrow. Bone marrow-derived cells (BMDCs) are among the key cell types in the microenvironment that are proposed to contribute to tumor malignancy, however the underlying mechanisms are poorly understood.

In this project, Dr. Joyce is investigating the roles of BMDC-supplied cathepsin proteases in promoting malignant progression and limiting therapeutic response. While the contribution of the microenvironment to tumor progression has recently gained importance, its role in modulating the response of tumors to therapy has hardly been explored. Dr. Joyce and her team believe that this area of study requires special attention and could have immediate implications for how we treat breast cancer. They have made the exciting recent finding that cathepsin-positive BMDCs are increased in the circulation of laboratory models treated with certain chemotherapeutic drugs. Their preliminary trials in a laboratory model of breast cancer indicate that inhibition of cathepsins in combination with chemotherapy greatly enhances its therapeutic efficacy. Thus, this research may ultimately lead to therapeutic strategies for enhancing the efficacy of existing FDA-approved drugs.

Bio:
Johanna Joyce is an Assistant Member in the Cancer Biology Program at Memorial Sloan Kettering Cancer Center, New York, and an Assistant Professor in Cornell University Graduate School of Medical Sciences. She received her Ph.D. in Biology from the University of Cambridge, England in 1999, and did her postdoctoral training in Dr. Douglas Hanahan's lab at UCSF. She joined MSKCC in December 2004, and was named to a Geoffrey Beene Junior Faculty Chair in 2007. Her research interests are to understand the mechanisms by which stromal cells in the tumor microenvironment regulate cancer development, metastasis, and response to therapy.