Scott Atwood, Ph.D.

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Research

The Atwood lab is interested in how stem cell heterogeneity drives epidermal homeostasis and disease. We focus on protein kinase regulation of signaling pathways and transcription factors, using models of skin development and basal cell carcinoma, to determine how kinases influence cell fate by controlling the genetic landscape of the cell.

Cancer Initiation and Progression

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, regression, 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 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. 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 defining the drivers of tumor regression, identifying and therapeutically targeting novel kinase-substrate interactions that drive tumor growth, understanding how recurrent mutations translate to functional consequences, and delineating how tumor cells interact with their environment.

Skin Stem Cell Fate Specification

Stem cells give rise to many complex tissues such as the skin and hair follicle by controlling cell fate specification. How epidermal stem cells choose their fate remains unclear. Our lab has identified robust heterogeniety in the basal stem cells of human skin through single cell RNA-sequencing that changes the way we appreciate how the human epidermis develops. We have identified four spatially distinct epidermal stem cell subpopulations that contribute to epidermal developoment and homeostasis. Projects in the lab include defining how epidermal stem cell populations are related by lineage, how they communicate, how they pattern the skin, and which population preferentially gives rise to hyperproliferative skin disorders such as psoriasis and basal cell carcinoma. 

Immune regulation of skin homeostasis and cancer

Phenotypically normal aged skin is often highly mutated with alterations in oncogenes and tumor suppressors that would induce tumor growth in mice. How skin prevents most tumor clones from growing past tissue boundaries remains unknown. We are currently using a BCC mouse model to define how the immune system monitors tumor clones and elicits an immune response to eradicate oncogenic outgrowths. When large BCC outgrowths do appear in aged skin, response to immunotherapy is highly variable. Traditionally thought to be a “cold” cancer that does not readily incite an immune response, immune-BCC interactions do occur but with far less frequency than other skin cancers. Using single cell RNA-sequencing approaches, analysis cell-cell communication, and mathematical modeling in late-stage tumors, we discovered potential biomarkers that may predict response to checkpoint immunotherapy. Projects in the lab include characterizing the immunogenicity of BCC, uncovering ways to therapeutically increase tumor immunogenicity, understanding how tumor-derived signals suppress the immune system, and defining how the immune system regulates tumor regression.

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Publications

See a complete list of publications at https://pubmed.ncbi.nlm.nih.gov/?term=scott+atwood&sort=date

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

• Distinct mechanisms for sebaceous gland self-renewal and regeneration provide durability in response to injury.
  Natalia A. Veniaminova**, Yunlong Jia**, Adrien Hartigan, Thomas J. Huyge, Shih-Ying Tsai, Marina Grachtchouk, Seitaro Nakagawa, Andrzej A. Dlugosz, Scott X. Atwood#, Sunny Y. Wong#
  Cell Reports. 2023. 42(9):113121.
• Single cell transcriptomics of human skin equivalent organoids
  Adam R. Stabell, Grace E. Lee, Yunlong Jia, Kirsten Wong, Shuxiong Wang, Ji Ling, Sandrine D. Nguyen, George L. Sen, Qing Nie, Scott X. Atwood
  Cell Reports. 2023. 42(5):112511.
• Screening cell-cell communication in spatial transcriptomics via collective optimal transport
  Zixuan Cang, Yanxiang Zhao, Axel Almet, Adam Stabell, Raul Ramos, Maksim Plikus, Scott X. Atwood, Qing Nie
  Nature Methods. 2023. 20(2):218-228.
• Single-cell analysis of human basal cell carcinoma reveals novel regulators of tumor growth and the tumor microenvironment
  Christian F. Guerrero-Juarez**, Gun Ho Lee**, Yingzi Liu, Shuxiong Wang, Matthew Karikomi, Yutong Sha, Rachel Y. Chow, Tuyen T.L. Nguyen, Venus Sosa Iglesias, Sumaira Aasi, Michael L. Drummond, Qing Nie, Kavita Sarin#, Scott X. Atwood#
  Science Advances. 2022. 8(23):eabm7981.
• Online engagement in an undergraduate cell biology course
  Eric Tarapore**, Justin F. Shaffer**, Scott X. Atwood
  Journal of College Science Teaching. 2022. 51(4):27-34.
• Exploiting enogenous enzymes for cancer-cell seletive metabolic labeling of RNA in vivo
  Samantha Beasley, Abigail Vandewalle, Monika Singha, Kim Nguyen, Whitney England, Eric Tarapore, Nan Dai, Ivan Correa Jr., Scott X. Atwood, Robert C. Spitale
  Journal of the American Chemical Society. 2022. 144(16):1085-7088.
• PI3K promotes basal cell carcinoma through kinase-induced p21 degradation
  Rachel Y. Chow, Ung Seop Jeon, Taylor M. Levee, Gurleen Kaur, Daniel P. Cedeno, Linda T. Doan, Scott X. Atwood
  Frontiers in Oncology. 2021. 11:668247.
• MTOR promotes basal cell carcinoma growth through atypical PKC
  Rachel Y. Chow, Taylor M. Levee, Gurleen Kaur, Daniel P. Cedeno, Linda T. Doan, Scott X. Atwood
  Experimental Dermatology. 2021. 30(3):358-366.
• Single cell transcriptomics of human epidermis identifies basal stem cell transition states
  Shuxiong Wang**, Michael L. Drummond**, Christian F. Guerrero-Juarez, Eric Tarapore, Adam L. MacLean, Adam R. Stabell, Stephanie C. Wu, Guadalupe Gutierrez, Bao T. That, Claudia A. Benavente, Qing Nie#, Scott X. Atwood#
  Nature Communications. 2020. 11(1): 4239.
• Divergent resistance mechanisms to immunotherapy explain responses in different skin cancers
  Emmanuel Dollinger**, Daniel R. Bergman, Peijie Zhou, Scott X. Atwood#, Qing Nie#
  Cancers. 2020. 12(10): 2946.
• AP-1 and TGFB cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma
  Catherine D. Yao, Daniel Haensel, Sadhana Gaddam, Tiffany Patel, Scott X. Atwood, Kavita Y. Sarin, Ramon J. Whitson, Siegen McKellar, Gautam Shankar, Sumaira Aasi, Kerri Rieger, Anthony E. Oro
  Nature Communications. 2020. 11(1): 5079.
• 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.
• Noncanonical hedgehog pathway activation through SRF-MLK1 promotes drug resistance in basal cell carcinoma
  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, Eunice Y. Lee, S. Tyler Hollmig, Sumaira Z. Aasi, Kavita Y. Sarin, Matthew P. Scott, Ervin H. Epstein, Jean Y. Tang, Anthony E. Oro
  Nature Medicine. 2018. 24(3):271-81.
• 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.
• 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.
• 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.
• 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.
• RAS/MAPK activation drives resistance to Smo inhibition, metastasis and tumor evolution in Shh pathway-dependent tumors
  Xuesong Zhao, Tatyana Ponomaryov, Kimberly J. Ornell, Pengcheng Zhou, Sukriti K. Dabral, Ekaterina Pak, Wei Li, Scott X. Atwood, Ramon J. Whitson, Anne Lynn S. Chang, Jiang Li, Anthony E. Oro, Jennifer A. Chan, Joseph F. Kelleher, Rosalind A. Segal
  Cancer Research. 2015. 75(17):3623-35.
• Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition
  Yujie Tang, Sharareh Gholamin, Simone Schubert, Minde I. Willardson, Alex Lee, Pratiti Bandopadhayay, Guillame Bergthold, Sabran Masoud, Brian Nguyen, Nujsaubnusi Vue, Brianna Balansay, Furong Yu, Sekyung Oh, Pamelyn Woo, Spenser Chen, Anitha Ponnuswami, Michelle Monje, Scott X. Atwood, Ramon J. Whitson, Siddhartha Mitra, Samuel H. Cheshier, Jun Qi, Rameen Beroukhim, Jean Y. Tang, Rob Wechsler-Reya, Anthony E. Oro, Brian A. Link, James E. Bradner, Yoon-Jae Cho
  Nature Medicine. 2014. 20(7):732-40.
• 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.
• MIM and Cortactin antagonism regulates ciliogenesis and Hedgehog signaling
  Marina Bershteyn, Scott X. Atwood, Wei-Meng Woo, Mischa Li, Anthony E. Oro
  Developmental Cell. 2010. 19(2):270-83.
• 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.
• Cdc42 acts downstream of Bazooka to regulate neuroblast polarity through Par-6-aPKC
  Scott X. Atwood, Chiswili Chabu, Rhiannon R. Penkert, Chris Q. Doe, Kenneth E. Prehoda
  Journal of Cell Science. 2007. 120(Pt 18):3200-6.

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