Pharmacological Sciences

Assistant Professor, Pharmacological Sciences
emily@pharm.stonybrook.edu
4-3134
Breast Cancer Metastasis & Shotgun Proteomics

Metastasis, the process whereby tumor cells spread throughout the body, is the leading cause of death in breast cancer patients. However, the determinants of organ-specific metastasis are not well understood. The research focus of my lab is to understand the pathogenesis of breast cancer metastasis by identifying relevant proteins that are involved in organ specificity. We believe that protein expression profiles in breast cancer cells capable of organ-specific metastasis can be used to distinguish organ specificity among breast cancer cells, and that the differentially regulated proteins contribute to colonization of or survival within the individual target tissues.

Organ Specific Cancer Metastasis
Metastasis to distant organs is a highly specific process. The origin of the primary tumor seems to determine which distant organs will be colonized. For example, preferred organs for breast cancer metastasis are lymph nodes, bone, lung, brain, and liver. Typically, research on metastasis is performed based on in vivo assays in small animal models, as no single in vitro assay can recapitulate this process. Assays are normally divided into ones for experimental metastasis and ones for spontaneous metastasis. Experimental metastasis is analyzed by injecting tumor cells into the circulatory system and therefore measures only the last steps of the metastastic process, success in colonization of a secondary site. I have employed this assay to obtain brain, lung, and bone metastatic variant cancer cells derived from the original heterogeneous primary breast tumor cell line. Using this experimental metastasis model, I have found changes in the tumorgenecity of the cancer cells that successfully proliferate at sites of metastasis. Specifically, the genes and proteins expressed in those cells differ in part from those expressed by primary tumor cells. Moreover, the changes in expression differ accordingly to the individual metastatic site. These data indicate that the tumor cells are selected for or adapt to the new environments by initiating a unique program of transcriptional and translational regulation. Strikingly, I have found that this reprogramming of genes and protein expression includes factors that enable the cancer cells to respond to growth signals already present in the specific local environment of the secondary tissue.

Metastatic Cancer Stem Cells and Organ Specific Metastasis
Recent studies have described a small population of self-renewing and multipotent cells within tumors termed “cancer stem cells” that have been proposed to be the source of primary tumors and secondary metastases in many types of cancer. In my lab, studies are proposed to address two questions: i) is the phenotype of invasion and metastasis uniquely connected to the tumor stem cell phenotype? ii) does the tumor stromal niche act as a constituent of a feedback mechanism with tumor stem cells to control their growth? We will test the hypothesis that tissue specific signaling provides positive feedback signals in the metastatic tumor niche to facilitate the adaptation of metastatic cancer stem cells and support the formation of organ-specific metastasis. The findings from our studies will reveal potential mechanisms that breast cancer cells acquire to colonize and proliferate at specific organ sites. Once identified, differently regulated proteins that facilitate organ-specific metastasis will be invaluable therapeutic targets for developing approaches to prevent metastatic disease. Ultimately, we hope to generate new molecular insights into the organ specificity of breast cancer metastasis and novel therapeutic approaches.

Proteomic approach to characterize global proteome changes and post-translational modifications
To identify comprehensive protein profiles of complex protein mixtures such as mammalian cell lysates, we use a mass spectrometry-based proteomic approach to analyze highly complex mixture of proteins. First, the protein mixture is proteolytically cleaved in solution and the resulting peptide mixtures are resolved by high-resolution HPLC separations prior to acquisition of tandem mass spectra. Current research projects in my lab consist of quantitative and qualitative proteomic analysis using the LC-MS/MS approach.