Personalized medicine targets specific cancers by taking advantage of a tumors dependence on certain signaling pathways for growth. Mutations that activate the Hedgehog pathway drive growth of a variety of cancers including basal cell carcinoma (BCC) and medulloblastoma, accounting for up to 25% of all human cancer deaths. Despite the critical nature of Hedgehog signaling during development, how Hedgehog mediates tumor initiation, growth, and drug resistance remains poorly understood. For instance, use of drugs that target the Hedgehog pathway GPCR Smoothened are effective in treating advanced or metastatic BCC, however over 50% of advanced tumors harbor innate resistance and over 20% of tumors that initially respond to drug acquire resistance each year, illustrating the need for additional targets for therapy. Our lab has identified the oncogene atypical Protein Kinase C (aPKC) as a novel Hedgehog target gene and activator of Hedgehog signaling. aPKC forms a positive feedback loop by phosphorylating and activating the transcription factor GLI1, resulting in an increase in DNA binding and transcriptional activity. Additionally, our lab has identified that the majority of drug-resistance in BCC results from mutations in SMO that induce constitutive activity or disrupt drug interaction. Interestingly, sensitive and drug resistant BCCs magnify aPKC activity to drive high levels of pathway activation and therapeutic use of aPKC or GLI inhibitors selectively suppress Hedgehog signaling and tumor growth, suggesting the use of aPKC or GLI antagonists as viable options to treat drug-resistant tumors. Projects in the lab include determining how tumor cells regulate kinase activity, identifying novel kinase-substrate interactions that drive tumor growth, and creating novel inhibitors to target these pathways.
Stem cells give rise to many complex tissues such as the skin and hair follicle by controlling cell fate specification. Typically, stem cells set up a gradient of polarized components whose job is to organize intracellular signaling factors, allowing daughter cells to adopt specific fates and perform specialized functions. The conserved oncogene aPKC is found in virtually all polarized systems and serves as a master regulator of cell polarity and fate specification. A newly appreciated aspect of aPKC is the ability to phosphorylate transcription factors to regulate the genetic landscape of the cell. An open question is how posttranslational modifications control transcription factor function. Our lab has found that aPKC phosphorylates the C2H2 zinc finger domain of GLI1 to promote DNA binding and transcriptional activity, an exceedingly rare event that exerts a positive signal towards transcription factor function. Projects in the lab include exploring how phosphorylation generally regulates transcription factor activity, how kinase-transcription factor interactions specify the skin and hair follicle, and how cancers co-opt this developmental process to drive tumor growth.