Research Interests

Cancer progression

One of the emerging themes in cancer biology is the dependence of cancer subtypes on certain signaling pathways for continued tumor growth. For example, mutations that activate the Hh signaling pathway drive growth of a variety of cancers including basal cell carcinoma (BCC), medulloblastoma, pancreatic, prostate, and small cell lung cancer that account for up to 25% of all human cancer deaths. Despite the critical nature of Hh signaling, how Hh mediates tumor proliferation remains poorly understood. Use of Smo antagonists are effective in treating advanced or metastatic BCC, however early tumor resistance in about 20% of patients illustrates the need for additional targets for therapy. I have identified aPKC as a novel Hh target gene and activator of Hh signaling. aPKC forms a positive feedback loop by phosphorylating and activating Gli1, resulting in an increase in DNA binding and transcriptional activity. Smo antagonist-sensitive and resistant BCCs upregulate aPKC activity to drive high levels of Hh signaling for continued growth. Application of topical aPKC inhibitors suppress signaling and growth of murine tumors and Smo-resistant BCC cell lines, implicating aPKC as a new, tumor-selective therapeutic target for the treatment of Hh-dependent cancers. I am currently identifying new aPKC inhibitors, determining how cancer promotes kinase activity, and how substrate phosphorylation drives tumor growth.

 

Cell fate specification

Complex tissues and cellular architecture develop and are maintained by continual cell fate specification of progenitor cells. Progenitor cells set up a gradient of polarized components that function to organize interior and exterior cellular structures and signaling factors, allowing the cell to adopt specific fates and perform specialized functions. This process of cell polarity drives a diverse range of functions such as maintaining the epithelial barrier, cell-to-cell communication, motility, localized signaling, and cell fate specification. The conserved oncogene atypical Protein Kinase C (aPKC) is a master regulator of cell polarity and fate specification and is found in virtually all polarized systems. aPKC is part of a complex of proteins that include the PDZ domain protein Par6 and Rho GTPase Cdc42. I have shown that Cdc42 recruits and activates aPKC at the apical cortex of Drosophila neural stem cells. Once there, aPKC maintains the stem cell state in part by phosphorylating and segregating fate determinants such as Miranda and Numb to the differentiating daughter cell. In murine skin, aPKC controls polarized structures such as primary cilia and directs their signaling. I'm currently exploring aPKC's role in specifying murine basal keratinocytes, dermal cells, and how phosphorylation gives rise to cycling hair follicles.

 

Transcription factor regulation

Transcription factors (TFs) are an essential step in generating the cellular microenvironment that drives cell fate specification. TFs spatially and temporally bind DNA to transcribe the RNA that makes up the regulatory landscape of the cell. C2H2 zinc finger domains are a common element of many TFs that allow binding to DNA. Although C2H2 zinc fingers are regulated by a bevy of posttranslational modifications, protein cofactors, and RNA regulators to help control DNA binding and transcriptional activity, how specification of function is achieved is poorly understood. I have found that the C2H2 zinc finger domain of Gli1 is phosphorylated by aPKC, promoting DNA binding and transcriptional activity. As posttranslational modifications of zinc fingers that promote activity are exceedingly rare, I am currently investigating how phosphorylation alters Gli function and target site selection. I am also exploring how phosphorylation serves as a general regulatory mechanism of TF activity and how cancers co-opt this developmental process to drive tumor growth.