Scott Atwood, Ph.D.

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Research

The Atwood lab is interested in how cells choose their fate. We use models of skin 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.

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Publications

See a complete list of publications at http://www.ncbi.nlm.nih.gov/pubmed?term=atwood%20sx%5BAuthor%5D

Selected publications (** Denotes equal contribution, # Denotes co-corresponding authors)

• Loss of primary cilia drives switching from Hedgehog to Ras pathway and basal cell to squamous cell carcinoma
  Francois Kuonen**, Noelle E. Hiskey**, Gautam Shankar, Prajakta Jaju, Ramon J. Whitson, Kerri E. Rieger, Scott X. Atwood, Kavita Y. Sarin, Anthony E. Oro
  Journal of Investigative Dermatology. 2019. Accepted.
• Actin polymerization controls cilia-mediated signaling
  Michael L. Drummond, Mischa Li, Eric Tarapore, Tuyen T.L. Nguyen, Baina J. Barouni, Shaun Cruz, Kevin C. Tan, Anthony E. Oro#, Scott X. Atwood#
  Journal of Cell Biology. 2018. 217(9):3255-66.
• MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias
  Alexander S. Brown, Pratap Meera, Banu Altindag, Ravi Chopra, Emma Perkins, Sharan Paul, Daniel R. Scoles, Eric Tarapore, Jessica Magri, Haoran Huang, Mandy Jackson, Vikram G. Shakkottai, Thomas S. Otis, Stefan M. Pulst, Scott X. Atwood#, Anthony E. Oro#
  Proceedings of the National Academy of Sciences. 2018. 115(52):E12407-E12416.
• Illuminating alternative strategies to treat targeted chemotherapy-resistant sporadic basal cell carcinoma
  Tuyen T.L. Nguyen and Scott X. Atwood
  Journal of Investigative Dermatology. 2018. 138(5):1017-19.
• Non-canonical hedgehog pathway activation by MLK1/SRF promotes drug resistance in basal cell carcinomas
  Ramon J. Whitson, Alex Lee, Nicole M. Urman, Amar Mirza, Catherine Y. Yao, Alexander S. Brown, Jiang R. Li, Gautam Shankar, Micah A. Fry, Scott X. Atwood, S. Tyler Hollmig, Sumaira Z. Aasi, Kavita Y. Sarin, Ervin H. Epstein, Jean Y. Tang, Anthony E. Oro
  Nature Medicine. 2018. 24(3):271-81.
• sm”FISH”ing for Hedgehog
  Michael L. Drummond and Scott X. Atwood
  Journal of Investigative Dermatology. 2017. 137(1):13-5.
• Atypical Protein Kinase C – Histone Deacetylase 1 inhibitors cooperate in basal cell carcinoma treatment
  Amar N. Mirza, Micah A. Fry, Nicole M. Urman, Scott X. Atwood, Jon Roffey, Gregory R. Ott, Bin Chen, Alex Lee, Alexander S. Brown, Sumaira Z. Aasi, Tyler Hollmig, Mark A. Ator, Bruce D. Dorsey, Bruce R. Ruggeri, Craig A. Zificsak, Marina Sirota, Jean Y. Tang, Atul Butte, Ervin Epstein, Kavita Y. Sarin#, Anthony E. Oro#
  JCI Insight. 2017. 2(21). pii: 97071.
• 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. 139(6):2148-51.
• 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.
• aPKC phosphorylates Miranda to polarize fate determinants during neuroblast asymmetric cell division
  Scott X. Atwood and Kenneth E. Prehoda
  Current Biology. 2009. 19(9):723-9.

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