Jason Mills, M.D., Ph.D.

DEPARTMENT OF Pathology & Immunology
Keywords: stem cells, pathogenesis, differentiation, bioinformatics, cancer, stomach

My lab is using a multipronged approach to understand the cellular and molecular details of adult stem cell biology in the mouse and human stomach. We are interested both in normal developmental pathways from the multipotent stem cell and in uncovering the aberrations that occur when those pathways go awry (e.g., in stomach cancer). In particular, we have focused recently on how mucus-secreting neck cells arise from a multipotent gastric epithelial stem cell and then undergo a dramatic differentiation into digestive-enzyme-secreting zymogenic (chief) cells. In one set of experiments, we combined mouse genetics, human histopathology and bioinformatic promoter/expression analyses, as well as in vitro mechanistic studies to identify the first gene, the bHLH transcription factor Mist1, required for normal maturation of zymogenic cells, and we have shown that this gene is lost during progression to chronic gastric atrophy, a pre-cursor state for gastric carcinoma. Interestingly, expression of Mist1 seems to correlate positively with migration away from the neck cell zone, which is rich in the morphogen Sonic Hedgehog (Shh). Our recent experiments show that Mist1 expression is lost when Hedgehog and/or Bmp signaling are inducibly disrupted in adult mice. We are using transgenic and knock-out mice to assess how Mist1 and other transcription factors, such as Foxa1 and Xbp1, coordinate with Hedgehog and Bmp signaling to regulate the complex epithelial developmental pathways that occur on a daily basis in the adult stomach. We are also actively studying expression of the transcription factors and morphogens we identify in our mouse model in human tissue samples and manipulating expression in vivo in human gastric cancer cell lines.