Research in Women's Health
Dr. Adam J. Krieg completed his undergraduate degree in Biochemistry and Biophysics from Orgeon State University, Corvallis OR, and his Ph.D. in Biochemistry from the University of Illinois, Urbana-Champaign, IL. He then went on to complete his Post-Doctoral Fellowship from Stanford University, Stanford, CA.
My research focuses primarily on characterizing the gene expression patterns induced in cancer cells in response to tumor hypoxia. Tumor hypoxia is a phenomenon that occurs once tumor cells expand farther than 100 microns from a functional blood vessel. Beyond this key distance, oxygen and nutrients are consumed faster than the rate of diffusion, resulting in a gradient of reduced oxygen (hypoxia). In response to this hypoxic microenvironment, cancer cells induce a significant number of adaptive pathways to promote cell survival (anaerobic metabolism and apoptosis suppression), restore oxygen to the cell (angiogenesis)s, and migrate to more congenial environments (metastasis). One of the predominant mechanisms utilized by cells to respond to hypoxia is the Hypoxia-Inducible Factor family of transcription factors (HIFs). The HIFs are master regulators of the hypoxic response, regulating genes that contribute to the growth of new blood vessels, promote the cellular transition to anaerobic glycolysis, promote cell invasion and migration. Genes regulated by HIFs are correlated with poor prognosis in many cancers, but also make unique targets for biological therapies. For instance, Bevacisumab targets the action of the classic HIF target gene Vascular Endothelial Growth Factor (VEGF), and is one of the more successful biological therapies. Thus improving our understanding of how the hypoxic microenvironment facilitates tumor progression may reveal yet more novel therapeutic approached to suppress the native adaptive response in tumor cells.
My most significant contribution to the study of hypoxic gene expression has probably been the discovery that several histone demethylases are directly regulated by HIF-1α, and that this regulation influences the growth of tumors through the hypoxic regulation of other tumorigenic genes (Krieg AJ, Rankin EB, Chan DA, Razorenova OV, Fernandez S, Giaccia AJ. Regulation of the histone demethylase JMJD1A by HIF-1α enhances hypoxic gene expression and tumor growth. Mol Cell Biol. 2010 Jan;30(1):344-53. PMID: 19858293). Thus, these histone demethylases are secondary responders of the hypoxic response, comprising a mechanism to extend and enhance the initial effects of HIF activity in the tumor and surrounding tissues. These histone demethylases regulate cell behavior at the epigenetic level, i.e. at the level of gene regulatory phenomena, to regulation expression of genes that contribute to tumor growth. Induction of histone demethylases by hypoxia provides a mechanism to "fix" the hypoxic phenotype in a cancer cell, stabilizing the aggressive behavior induced in response to oxidative stress, and providing novel targets to suppress tumor growth.
Currently, my laboratory is characterizing the expression of hypoxia-inducible histone demethylases in epithelial ovarian cancer (EOC), a disease characterized by a highly metastatic and recurrent phenotype, with extremely poor patient prognosis. We have determined that one of these demethylases, KDM4B (JMJD2B), regulates genes and pathways with clear association with metastasis, providing a novel mechanism underlying the process of malignant ascites, the predominant cause of the rapid abdominal dissemination in EOC patients. We believe that the genes regulated by KDM4B, particularly secreted proteins, provide a unique opportunity to develop therapies to suppress peritoneal EOC recurrence after initial debulking surgeries. We are currently dissecting the molecular mechanisms regulated by KDM4B in EOC cells, linking the actions of histone demethylation to the expression of tumorigenic genes, and characterizing the ability of EOC cells lacking KDMB expression to metastasis in vitro and in vivo. Additionally, we have determined that KDM4B is robustly expressed in the female and male reproductive tracts, providing a unique opportunity to convert the tumor biology skills we have developed to the study of epigenetic mechanisms inm reproductive biology. To achieve all of these ends, we have made heavy use of the KU Cancer Center's Biospecimen Core Resource Facility to acquire patient-derived samples (in collaboration with Dr. Andrew Godwin, PhD and Dr. Jeremy Chien, PhD), and initiated two IRB approved protocols to collect and analyze endometrial and ovarian tissues from the KUMC OB/GYN department (in collaboration with Dr. Sacha Krieg, MD PhD). By following my interests in basic gene expression mechanisms and cellular response to stress, my laboratory is poised to make significant contributions to both cancer biology and reproductive biology.
Adam Krieg, PhD