Dr. Steven Zhan received his PhD in Biochemistry from Columbia University at New York City in 1988 and started his postdoctoral training at the National Cancer Institute and the Holland Laboratory at the American Red Cross. He began his independent research beginning at the San Francis Hospital, University of Connecticut, and then American Red Cross. In 2004, he joined as a faculty member of the Hormone Responsive Cancers Program within the University of Maryland Marlene and Stewart Greenebaum Cancer Center Program in Oncology. As such, he collaborates with research and clinical investigators in the Center to develop innovative approaches to diagnosis, treatment and prevention of breast cancers. Dr. Zhan's research centers on characterizing cortactin and metastasis suppressor gene 1 (MTSS1), the two genes that are associated with breast cancer metastasis, and on developing therapeutic agents for their gene products.
Metastasis, which describes spreading and subsequent colonization of primary tumor cells at distant tissues, is the major cause for the mortality of most cancer patients, including breast cancers. Like normal leukocytes, metastasis of tumor cells encompass at least two cell biological programs, an intracellular one that provides a mechanical force for cells to undergo shape changes, invade local tissues, enter into the circulation, and exit from the circulation; and an extracellular one that provides a signal for the direction of disseminated tumor cells targeting at a specific site.
At the molecular level, the mechanic force is largely generated by the assembly of the monomeric actin into branched filaments at cell leading edges; whereas the directional signal is commonly carried by the gradient of a chemokine released from metastatic sites. One of the questions we have been interested is how tumor cells are endowed with an intrinsic ability to orchestrate these two programs in favor of their metastasis.
In the past decade, we have been focusing on two genes: cortactin and missing in metastasis (MIM or MTSS1), both of which are often aberrantly expressed in metastatic cells in an opposite manner. While cortactin is commonly overexpressed because of gene amplification at the chromosome 11q13, MTSS1 expression often enters into silence along with increased cell migration and tumor metastasis. To understand the exact role of these two molecules in metastatic programs, we developed a variety of biochemical, cellular and animal models analyzing the properties of cortactin and MTSS1. Using these models, we demonstrated that cortactin is implicated in the assembly of branched actin filaments within the leading edge of motile cells.
We also evidenced that MTSS1 promotes membrane deformation and facilitates the internalization of receptors on the cell surface. In the effort to identify the pathophysiological role of MTSS1, we recently found the evidence that depletion of MTSS1 in mice favors malignant progression of B cells and modulates the trafficking of hematopoietic stem and progenitor cells through increasing the surface expression of CXCR4, a chemokine receptor that is crustal for the homeostasis of leukocytes and for directing breast cancerous cells metastasized into the bone.
Interestingly, MTSS1 binds to cortactin and potentiates the cortactin-mediated actin assembly, suggesting that these two molecules converge upon the pathways utilized by the intracellular and extracellular programs for metastasis. The current of the research is centered on delineating the pathway for MTSS1 and cortactin to regulate the response of tumor cells to chemokines and on exploring a potential to compromise metastasis by developing agents targeting this pathway.
Lab Techniques and Equipment:
The laboratory exploits routinely the techniques commonly used in molecular cell biology, biochemistry and molecular oncology. In collaboration with colleagues in the campus, recent works involve preparation of gene knockout mice, bone marrow transplant in mice, and various hematological assays analyzing the trafficking of hematopoietic stem and progenitors. We are also working on using CRISPR/Cas9 to generate knockout and knockin cells and animals and nanotechiques to delivery anti-cancer drugs.