Professor

Joined the faculty: 2008

Affiliations: Mary Babb Randolph Cancer Center

Teaching: BMS 730

Office: 212 Byrd Biomedical Bldg.
Phone: (304) 293-5246
Fax: (304) 293-4667
Email: mruppert@hsc.wvu.edu

Research Focus:  Initiation of epithelial cancers of the skin and breast; signaling by KLF4 and Gli1

Research Interests:  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.

  References:

• Jiang W, Deng W, Bailey SK, Nail CD, Frost AR, Brouillette WJ, Muccio DD, Grubbs CJ, Ruppert JM, Lobo-Ruppert SM. Prevention of KLF4-mediated tumor initiation and malignant transformation by UAB30 rexinoid. Cancer Biol. Ther 2009;8:285-94.
   
• Jiang W, Lobo-Ruppert SM, Ruppert JM. Bad things happen in the basal layer: KLF4 and squamous cell carcinoma. Cancer Biol. Ther 2008;7(5):783-5. PM:18424916.
   
• Li, X., Deng, W., Lobo-Ruppert, S. M., and Ruppert, J. M. Gli1 acts through Snail and E-cadherin to promote nuclear signaling by β-catenin. Oncogene, 26: 4489-4498, 2007.
   
• Mukherjee S, Frolova N, Sadlonova A, Novak Z, Steg A, Page GP, Welch DR, Lobo-Ruppert SM, Ruppert JM, Johnson MR and Frost AR. Hedgehog signaling and response to cyclopamine differs in epithelial and stromal cells in benign breast and breast cancer. Cancer Biology and Therapy 5: 674-83, 2006.
   
• Li X, Deng W, Nail CD, Bailey SK, Kraus MH, Ruppert JM, and Lobo-Ruppert SM. Snail induction is an early response to Gli1 that determines the efficiency of epithelial transformation. Oncogene 25: 609-21, 2006.
   
• Huang C C, Liu Z, Li X, Bailey SK, Nail CD, Foster, KW, Frost, AR, Ruppert, JM, and Lobo-Ruppert, SM. KLF4 and PCNA identify stages of tumor initiation in a conditional model of cutaneous squamous epithelial neoplasia. Cancer Biology and Therapy, 4: 1401-1408, 2005.
   
• Foster KW, Liu Z, Nail CD, Li X, Fitzgerald TJ, Bailey SK, Frost AR, Louro ID, Townes TM, Paterson AJ, Kudlow JE, Lobo-Ruppert SM, and Ruppert JM. Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia. Oncogene 24: 1491-1500, 2005.