Using Pluripotent Stem Cells to Identify Embryonic Mechanisms Mediating Cancer Aggressiveness Reveals a Novel Role for Cell Surface GRP78 in Regulating Critical Stem Cell and Cancer Functions

Many studies have demonstrated that certain cell populations within the tumor display an early embryonic or stem-like gene expression signature, and these populations have been correlated to cancer metastasis and overall disease aggressiveness. Identifying the specific stem-like mechanisms utilized by cancer cells, and devising strategies to target these mechanisms, remains an ongoing challenge. To gain insight into the stem-like mechanisms that cancer cells exploit to achieve their aggressive oncogenic phenotypes, we utilized both induced pluripotent stem cells (iPSCs) and cancer cells in our studies. The contribution of this dissertation research provides novel insight into cell surface GRP78, a protein that our findings suggest marks a stem-like population of aggressive breast cancer cells that has metastatic potential in vitro and in vivo. We further show that cell surface GRP78 regulates cell migration in iPSCs and cancer cells by cooperating with Dermcidin through regulation of Wnt signaling. Lastly, we demonstrate that cell surface GRP78 is a specific and effective targeting moiety on stem cells and cancer cells, by developing a novel liposome nanoparticle drug delivery system for cancer therapeutic and regenerative medicine applications.