Description of Research Expertise

Epithelial biology
Gene regulatory control of epidermal homeostasis
Epithelial oncogenesis
Tissue models of human malignancy

Description of Research:
The Ridky Lab uses genetically-defined, engineered epithelial tissues as an experimental platform to study pathways driving human cancer initiation, stromal invasion, tumor-stroma interaction, metastasis, and maintenance of cancer stem cells. Tissue models of invasive malignancy are used to identify and validate new targets for potential therapeutics. To maximize the physiologic and medical relevance of our efforts, we develop experimental human tissue systems based on normal primary human cells established within an architecturally faithful native 3-D environment incorporating intact mesenchymal stroma and living stromal cells. Progression to cancer is driven by genetic changes initially identified in spontaneous tumors in humans and specifically engineered into the model tissues. Many experiments are conducted entirely in this organotypic environment, while in vivo studies utilize immunodeficient mice as hosts for the engineered tissues. These new models allow up to 10 alleles or more to be altered simultaneously in 1-2 days, permitting genetic experiments with an unprecedented degree of rapidity and complexity exceeding that previously possible in traditional genetic experimental organisms, such as transgenic mice. These new genetic models, which we refer to as "Multifunctional Human Tissue Genetics", have allowed us to directly convert multiple normal human tissues into invasive cancer via targeted, specific alterations in defined, medically-relevant genetic networks. Bioinformatics-intensive systems biology approaches are used to identify centrally-acting elements that are likely important for promoting cancer progression. To determine functional roles for specific tumor cell or stromal cell-intrinsic factors, we employ various genetic and protein level interventions, including multiplexed expression of tumor-associated mutant oncogenic drivers, tumor suppressors, and conditionally active proteins. Disruption of primary oncogenic signaling and non-oncogene addicted (NOA) pathways is achieved via RNA interference (RNAi), as well as chemical small molecule inhibitors and protein based biologic agents as a foundation for development of targeted molecular therapeutics.

Lab Personnel:
Andrew McNeal - Research Specialist
Emily Schapira - UPenn (2013)
Kevin Liu - UPenn (2013)
Vihang Nakhate - UPenn (2014)
Seung Ja Oh - Postdoctoral fellow

Lab Web Page:
http://www.med.upenn.edu/ridkylab/

Selected Publications

Natale CA, Mercado S, Zhuang R, Aguirre-Portolés C, Olayide I, Arnatt CK, Seykora JT, Garyantes TK, Luke W, Ridky TW.: LNS8801: An enantiomerically pure agonist of the G protein-coupled estrogen receptor suitable for clinical development Cancer Res Commun : 2025.

Marinaro C, Sauer J, Natale CA, Ridky T, Chen S.: An In Vivo Study of LNS8801, a GPER Agonist, in a Spontaneous Melanoma-Prone Mouse Model, TGS Pigment Cell Melanoma Res : 2025.

Lee I, Doepner M, Weissenrieder J, Majer AD, Mercado S, Estell A, Natale CA, Sung PJ, Foskett JK, Carroll MP, Ridky TW.: LNS8801 inhibits Acute Myeloid Leukemia by Inducing the Production of Reactive Oxygen Species and Activating the Endoplasmic Reticulum Stress Pathway Cancer Res Commun 3 : 1594-1606,2023.

Hatterschide J, Natale CA, Ridky TW, White EA.: Monitoring cell fate in 3D organotypic human squamous epithelial cultures STAR Protoc 4 : 102101,2023.

Kohli J, Ge C, Fitsiou E, Doepner M, Brandenburg SM, Faller WJ, Ridky TW, Demaria M.: Targeting anti-apoptotic pathways eliminates senescent melanocytes and leads to nevi regression Nat Commun 13 : 7923,2022.

Doepner M, Lee I, Natale CA, Brathwaite R, Venkat S, Kim SH, Wei Y, Vakoc CR, Capell BC, Katzenellenbogen JA, Katzenellenbogen BS, Feigin ME, Ridky TW.: Endogenous DOPA inhibits melanoma through suppression of CHRM1 signaling Sci Adv 8 : eabn4007,2022.

Aguirre-Portolés C, Payne R, Trautz A, Foskett JK, Natale CA, Seykora JT, Ridky TW.: ZIP9 Is a Druggable Determinant of Sex Differences in Melanoma Cancer Res 81 : 5991-6003,2021.

Pharmacologic activation of the G protein-coupled estrogen receptor inhibits pancreatic ductal adenocarcinoma, Christopher A. Natale, Jinyang Li, Tzvete Dentchev, Brian C. Capell, John T. Seykora, Ben Z. Stanger, Todd W. Ridky: Pharmacologic activation of the G protein-coupled estrogen receptor inhibits pancreatic ductal adenocarcinoma Cellular and Molecular Gastroenterology and Hepatology : 2020 .

Monteleon Christine L, Lee In Young, Ridky Todd W: Exophilin-5 supports lysosome-mediated trafficking required for epidermal differentiation. The Journal of investigative dermatology 139 (10): 2219-2222.e6,2019.

Lee Vivian, Gober Michael D, Bashir Hasan, O'Day Conor, Blair Ian A, Mesaros Clementina, Weng Liwei, Huang Andrew, Chen Aaron, Tang Rachel, Anagnos Vince, Li JiLon, Roling Sophie, Sagaityte Emilija, Wang Andrew, Lin Chenyan, Yeh Christopher, Atillasoy Cem, Marshall Christine, Dentchev Tzvete, Ridky Todd, Seykora John T: Voriconazole enhances UV-induced DNA damage by inhibiting catalase and promoting oxidative stress. Experimental dermatology 29 (1): 29-38,2019.

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Academic Contact Information

Department of Dermatology
University of Pennsylvania
1010 Biomedical Research Building
421 Curie Blvd


Philadelphia, PA 19104
Phone: 215-573-5709
Patient appointments: 800-789-7366