3-D Human Cancer Models, Cancer Invasion and Metastasis, Stem Cells, Tumor-Stroma Interaction, Skin Pigmentation, Targeted Therapeutics
The Ridky Lab uses genetically-defined, engineered epithelial tissues as an experimental platform to study pathways driving human cancer initiation, tumor-stroma interaction, invasion and metastasis, maintenance of cancer stem cells, and regulation of skin pigmentation. Tissue engineered 3-dimensional skin grafts are used to identify and validate new targets and 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 10 alleles or more to be altered simultaneously in 1-2 days, enabling genetic experiments not possible in transgenic mice. These new genetic models 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, and high-throughput robotic molecular screening are used to identify elements that are likely important for regulating tissue homeostasis. To determine functional roles for specific epithelial or stromal 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) and CRISPR-Cas9 gene editing, as well as chemical small molecule inhibitors and protein based biologic agents as a foundation for development of targeted molecular therapeutics.
New potential therapeutic agents discovered in our lab are patent protected and licensed to our Penn sponsored biotech company Linnaeus Therapeutics Inc. Linnaeus collaborates with us to conduct additional mechanistic and preclinical efficacy studies to extend the scope of the intellectual property, and also with outside contract research organizations to perform the preclinical safety, formulation, and pharmacokinetic studies required for human trials.