Barbara Mueller Ph.D., Associate Professor

Dr. Mueller's Publications
bmueller@skcc.org

Barbara M. Mueller, PhD

Biology of Cancer Metastasis

The research in the Mueller laboratory aims to understand cancer metastasis with a focus is on the crosstalk between cancer cells and the host environment. The laboratory is interested in basic research and in topics critical to patient care.
One focus of the laboratory is the role of the coagulation proteases and their receptors in cancer progression and metastasis. They have defined relevant tissue factor (TF)-driven signaling pathways through protease-activated receptors (PAR) and now 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. These studies are conducted in collaboration with the Ruf laboratory at The Scripps Research Institute.
Another project uses a novel phage display methodology for the identification of cell surface biomarkers in metastasis competent cancer cells. 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. 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. The 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 project is a collaborative effort with the Baird laboratory at UCSD.
The Mueller laboratory also interacts with the Brain Tumor Program at SKCC led by Dr. Kruse. Together they are testing whether therapeutic modalities that the Kruse group is developing for the treatment of primary gliomas are useful for cancer metastatic to the brain. These modalities include immune therapy, namely allo-reactive cytotoxic T cells as well as gene therapies. Brain metastasis is a major problem in many types of cancer including breast cancer and melanoma, and existing therapies are woefully ineffective.

The aim is 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 the Mueller Lab's 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.