Michael Ruppert, MD/PhD

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.

Publications

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.

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.

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.

Farrugia MK, Sharma SB, Lin CC, McLaughlin SL, Vanderbilt DB, Ammer AG, Salkeni MA, Stoilov P, Agazie YM, Creighton CJ, Ruppert JM. "Regulation of anti-apoptotic signaling by Kruppel-like factors 4 and 5 mediates lapatinib resistance in breast cancer." Cell Death Dis. 2015;6:e1699

Lin CC, Sharma SB, Farrugia MK, McLaughlin SL, Ice RJ, Loskutov YV, Pugacheva EN, Brundage KM, Chen D, Ruppert JM. "Kruppel-like factor 4 signals through microRNA-206 to promote tumor initiation and cell survival." Oncogenesis. 2015;4:e155

Sharma SB, Ruppert JM. "MicroRNA-based therapeutic strategies for targeting mutant and wild type RAS in cancer." Drug Dev.Res. 2015;76(6):328-342.

Sharma SB, Lin CC, Farrugia MK, McLaughlin SL, Ellis EJ, Brundage KM, Salkeni MA, Ruppert JM. "microRNAs-206 and -21 cooperate to promote RAS-ERK signaling by suppressing the translation of RASA1 and SPRED1." Mol Cell Biol. 2014;34(22):4143-4164.

Lin CC, Liu LZ, Addison JB, Wonderlin WF, Ivanov AV, Ruppert JM. "A KLF4-miRNA-206 autoregulatory feedback loop can promote or inhibit protein translation depending upon cell context." Mol Cell Biol. 2011;31(12):2513-2527.

Jiang W, Deng WT, 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(3):289-298.

Liu Z, Teng L, Bailey SK, Frost AR, Bland KI, LoBuglio AF, Ruppert JM, Lobo-Ruppert SM. "Epithelial transformation by KLF4 requires Notch1 but not canonical Notch1 signaling." Cancer Biol Ther. 2009;8(19)