Atwood, Scott - University of California, Irvine - Department of Developmental and Cell Biology

研究领域

Cell fate in development and cancer The Atwood lab is interested in how cells choose their fate. We use models of skin and hair follicle development and skin cancer to determine how kinases control the genetic landscape of the cell to influence fate. Cancer initiation and progression 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 cell fate specification 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.

近期论文

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Cell-selective bioorthogonal metabolic labeling of RNA Kim Nguyen**, Michael Fazio**, Miles Kubota, Sarah Nainar, Chao Feng, Xiang Li, Scott X. Atwood, Timothy W. Bredy, Robert C. Spitale Journal of the American Chemical Society. 2017. doi:10.1021/jacs.6b11401. Tumor-derived Suppressor of Fused mutations reveal Hedgehog pathway interactions Nicole M. Urman, Amar Mirza, Scott X. Atwood, Ramon J. Whitson, Kavita Y. Sarin, Jean Y. Tang, Anthony E. Oro PLoS One. 2016. 11(12):e0168031. Combined treatment with arsenic trioxide and itraconazole inhibits the Hedgehog pathway in patients with refractory metastatic basal cell carcinoma: results from a pilot trial Mina S. Ally, Katherine Ransohoff, Kavita Sarin, Scott X. Atwood, Melika Rezaee, Irene Bailey-Healy, Jynho Kim, Philip A. Beachy, Anne Lynn S. Chang, Anthony Oro, Jean Y. Tang, A. Dimitrios Colevas JAMA Dermatology. 2016. 152(4):452-6. Smoothened variants explain the majority of drug resistance in basal cell carcinoma Scott X. Atwood**, Kavita Y. Sarin**, Ramon J. Whitson, Jiang R. Li, Geurim Kim, Melika Rezaee, Mina S. Ally, Jinah Kim, Catherine Yao, Anne L.S. Chang, Anthony E. Oro#, Jean Y. Tang# Cancer Cell. 2015. 27(3):342-53. Rolling the genetic dice: neutral and deleterious Smoothened mutations in drug-resistant basal cell carcinoma Scott X. Atwood, Kavita Y. Sarin, Jiang R. Li, Catherine Yao, Nicole M. Urman, Anne L.S. Chang, Jean Y. Tang, Anthony E. Oro Journal of Investigative Dermatology. 2015. 135(8):2138-41. Advanced treatment for basal cell carcinomas Scott X. Atwood, Ramon J. Whitson, Anthony E. Oro Cold Spring Harbor Perspectives in Medicine. 2014. 4(7):a013581. GLI activation by atypical protein kinase C iota/lambda regulates the growth of basal cell carcinomas Scott X. Atwood#, Mischa Li, Alex Lee, Jean Y. Tang, Anthony E. Oro# Nature. 2013. 494(7438):484-8. Hedgehog pathway inhibition and the race against tumor evolution Scott X. Atwood, Anne L.S. Chang, Anthony E. Oro Journal of Cell Biology. 2012. 199(2):193-7.