Barbara Mueller Ph.D., Professor

Dr. Mueller's Publications
bmueller@skcc.org

Barbara M. Mueller, PhD

Biology of Cancer Metastasis

Our research aims to understand cancer metastasis and to address issues critical to patient care. The goal of one of our projects is the identification of metastasis competent breast cancer cells. Metastasis to distant organs is a major cause of death for breast cancer patients. Yet, paradoxically, metastasis is an inefficient process and most cells in primary tumors, and even most tumor cells that disseminate from primary tumors, fail to complete the metastatic process. We hypothesize that tumor cells with metastatic competence are a distinct subset that expresses specific cell surface receptors involved in the multi-step process of metastasis. These receptors, while critical for metastasis, are not necessarily expressed in the cells in established metastases, reminiscent of temporal, selective gene expression in other cellular differentiation processes that occur during normal development. We are using a novel phage display methodology to identify the phenotype of breast cancer cells with metastatic competence. It is based on the observation that phage can enter mammalian cells by receptor-mediated processes and that phage DNA persists in infected cells for weeks. A heterogeneous cancer cell population is labeled at t=0 with phage displaying a library of peptide ligands. After the cells have completed the process of metastasis, phage DNA encoding the ligand that enabled the phage to enter the original cell can be recovered and analyzed. The extraordinary power of this genetic tagging approach resides in its ability to capture biomarking signatures of the original cells, irrespective of whether these biomarkers are lost in differentiation. Our goal is to identify and validate a unique biomarking signature of metastasis competent breast cancer cells, to discover thereby new prognostic markers and ultimately to develop biological therapies that can be used in combination with or instead of cytotoxic therapies. This can impact breast cancer because the lack of good prognostic markers for metastatic disease leads to unnecessary treatment and the lack of effective therapies for early or established metastasis is a major challenge to the cure of poor prognosis patients.

Another focus of our research remains the role of the tissue factor (TF)-initiated coagulation pathways in cancer development, angiogenesis and metastasis. We have defined relevant TF-driven signaling pathways through protease-activated receptors (PARs) and are identifying the underlying signaling mechanisms using transgenic and transplanted cancer models. One goal is to determine whether TF and PARs can be therapeutic targets in cancer, particularly if treatments can be developed that inhibit signaling rather than procoagulant function.