Gene regulatory control of epidermal homeostasis
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.
Andrew McNeal - Research Specialist
Emily Schapira - UPenn (2013)
Kevin Liu - UPenn (2013)
Vihang Nakhate - UPenn (2014)
Seung Ja Oh - Postdoctoral fellow
Lab Web Page:
Natale Christopher A, Duperret Elizabeth K, Zhang Junqian, Sadeghi Rochelle, Dahal Ankit, O'Brien Kevin Tyler, Cookson Rosa, Winkler Jeffrey D, Ridky Todd W: Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors. eLife 5, Apr 2016.
Cárdenas César, Müller Marioly, McNeal Andrew, Lovy Alenka, Jaňa Fabian, Bustos Galdo, Urra Felix, Smith Natalia, Molgó Jordi, Diehl J Alan, Ridky Todd W, Foskett J Kevin: Selective Vulnerability of Cancer Cells by Inhibition of Ca(2+) Transfer from Endoplasmic Reticulum to Mitochondria. Cell reports 14(10): 2313-24, Mar 2016.
Capell Brian C, Drake Adam M, Zhu Jiajun, Shah Parisha P, Dou Zhixun, Dorsey Jean, Simola Daniel F, Donahue Greg, Sammons Morgan, Rai Taranjit Singh, Natale Christopher, Ridky Todd W, Adams Peter D, Berger Shelley L: MLL1 is essential for the senescence-associated secretory phenotype. Genes & development 30(3): 321-36, Feb 2016.
Duperret Elizabeth K, Dahal Ankit, Ridky Todd W: Focal adhesion-independent integrin αv regulation of FAK and c-myc is necessary for 3D skin formation and tumor invasion. Journal of cell science 128(21): 3997-4013, Sep 2015.
Jessica McDonald: When Moles Go Bad: Penn Scientists Identify Commonly Lost Protein That Protects Against Melanoma. NPR, newsworks.org, WHYY radio August 2015.
Todd Ridky interviewed by Dan Loney: Moles and Melanoma. Knowledge@Wharton SIRIUS XM National Radio Broadcast
Host Dan Loney Interview with Todd Ridky regarding Moles, Melanoma, and P15 August 2015.
McNeal Andrew S, Liu Kevin, Nakhate Vihang, Natale Christopher A, Duperret Elizabeth K, Capell Brian C, Dentchev Tzvete, Berger Shelley L, Herlyn Meenhard, Seykora John T, Ridky Todd W: CDKN2B loss promotes progression from benign melanocytic nevus to melanoma. Cancer Discovery 5(10): 1072-85, Jul 2015.
Monteleon Christine L, McNeal Andrew, Duperret Elizabeth K, Oh Seung J, Schapira Emily, Ridky Todd W: IQGAP1 and IQGAP3 Serve Individually Essential Roles in Normal Epidermal Homeostasis and Tumor Progression. The Journal of investigative dermatology 135(9): 2258-65, Apr 2015.
Ridky Todd W, Cotsarelis George: Vismodegib resistance in basal cell carcinoma: not a smooth fit. Cancer cell 27(3): 315-6, Mar 2015.
Duperret EK, Ridky TW.: Kindler syndrome in mice and men. Cancer Biol Ther. 15(9): 1113-6, Jun 11 2014 Notes: [Epub ahead of print]
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Last updated: 05/19/2016
The Trustees of the University of Pennsylvania