Description of Research Expertise:
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:
Monteleon Christine L, Agnihotri Tanvir, Dahal Ankit, Liu Mingen, Rebecca Vito W, Beatty Gregory L, Amavaradi Ravi K, Ridky Todd W: Lysosomes support the degradation, signaling, and mitochondrial metabolism necessary for human epidermal differentiation. The Journal of investigative dermatology : 2018.
Natale Christopher A, Li Jinyang, Zhang Junqian, Dahal Ankit, Dentchev Tzvete, Stanger Ben Z, Ridky Todd W: Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade. eLife 7 : 2018.
Taylor Laura A, O'Day Conor, Dentchev Tzvete, Hood Kyle, Chu Emily Y, Ridky Todd W, Seykora John T: p15 Expression Differentiates Nevus from Melanoma. The American journal of pathology 186 (12): 3094-3099,2016.
Duperret Elizabeth K, Natale Christopher A, Monteleon Christine, Dahal Ankit, Ridky Todd W: The integrin αv-TGFβ signaling axis is necessary for epidermal proliferation during cutaneous wound healing. Cell cycle (Georgetown, Tex.) 15 (15): 2077-86,2016.
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 : 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): 2313-24,2016.
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): 321-36,2016.
Zhorov, Irina: Penn researchers use hormones to change skin tone NPR Radio (WHYY) Newsworks "The pulse" : 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): 3997-4013,2015.
Jessica McDonald: When Moles Go Bad: Penn Scientists Identify Commonly Lost Protein That Protects Against Melanoma NPR, newsworks.org, WHYY radio : 2015.
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