West Virginia University Health Science Center
United States of America
Works as Professor in Biochemistry
In vitro models of epithelia; Mouse models of cancer; Cell fate determination in epithelia; Sonic Hedgehog-Gli1 pathway; KLF4/GKLF pathway; Breast cancer; Non-melanoma skin cancer. We focus on the role of the zinc finger transcription factors KLF4/GKLF and Gli1 as regulators of chromatin structure, gene transcription and malignant transformation in epithelial cells, and their role in tumors such as breast cancer and skin cancer. These two oncogenes appear to function early in the genesis of carcinoma (e.g., Gli1 in cutaneous basal cell cancer, KLF4 in squamous cell carcinoma and breast cancer). We use a parallel approach, analyzing an in vitro epithelial model called RK3E cells, tetracycline-inducible transgenic mouse models, and tissues representing primary human tumors and normal tissues. In 1999 the laboratory reported the first successful use of epithelial cells as a host for oncogene isolation by a technique termed expression cloning, where cDNA libraries are expressed in an indicator line, and transforming oncogenes are identified by their phenotype. This study and our subsequent work identified KLF4 as a novel transcription factor oncogene and a potentially early effector of tumor initiation or progression in common adult cancers such as squamous cell carcinoma (SCC) and others. KLF4 is now recognized as a major determinant of the embryonic stem cell phenotype and may play a similar role in cancer cells. Subsequently we reported that induction of KLF4 in the skin rapidly induces lesions that resemble each of the stages of SCC tumor progression, identifying KLF4 as a candidate tumor initiator. Ongoing work in the lab includes analysis of a post-translational mechanism that regulates KLF4 expression levels and analysis of small molecules that specifically block KLF4 pathway activity in vitro and in vivo (e.g., retinoids). We have used microarrays in combination with inducible expression of Gli1 for functional analysis of the Hedgehog pathway, demonstrating roles for Snail, E-cadherin, Wnt ligands, b-catenin, mTOR and others as downstream effectors of Gli1. We demonstrated that Gli1 switches b-catenin from its role in normal cell adhesion to a role in cell growth mediated by canonical Wnt signaling.
Deng W, Vanderbilt DB, Lin CC, Martin KH, Brundage KM, Ruppert JM. "SOX9 inhibits beta-TrCP-mediated protein degradation to promote nuclear GLI1 expression and cancer stem cell properties." J.Cell Sci. 2015;128(6):1123-1138.
Addison JB, Koontz C, Fugett JH, Creighton CJ, Chen D, Farrugia MK, Padon RR, Voronkova MA, McLaughlin SL, Livengood RH, Lin CC, Ruppert JM, Pugacheva EN, Ivanov AV. "KAP1 promotes proliferation and metastatic progression of breast cancer cells." Cancer Res. 2015;75(2):344-355.
Farrugia MK, Vanderbilt DB, Salkeni MA, Ruppert JM. "Kruppel-like pluripotency factors as modulators of cancer cell therapeutic responses." Cancer Res. 2016;76(7):1677-1682.