1. Delaney, Sean P.; Julian, Lisa M.; Pietrobon, Adam; Yockell-Lelièvre, Julien; Doré, Carole; Wang, Ting T.; Doyon, Valerie C.; Raymond, Angela; Patten, David A.; Kristof, Arnold S.; Harper, Mary-Ellen; Sun, Hongyu; Stanford, William L. (2020) Human pluripotent stem cell modeling of tuberous sclerosis complex reveals lineage-specific therapeutic vulnerabilities.bioRxivHuman pluripotent stem cell modeling of tuberous sclerosis complex reveals lineage-specific therapeutic vulnerabilities
mTORC1 hyperactivation resulting from inactivating TSC2 mutations underlie the multi-system tumor disorder tuberous sclerosis complex (TSC) and the rare pulmonary neoplasm lymphangioleiomyomatosis (LAM). Mutation-bearing neural precursor cells (NPCs) lead to the formation of TSC brain tumors during development, while the cell of origin of TSC mesenchymal tumors such as LAM is unknown. We report the first model of multi-system TSC cell types, characterized by NPCs and neural crest cells (NCCs) differentiated in parallel from multiple engineered TSC2−/− human pluripotent stem cell (hPSC) lines. These cells successfully model defining phenotypes of neural and mesenchymal TSC, with transcriptomic signatures reflecting those observed in patient tumors, thus establishing TSC2−/− NCCs as a powerful model of LAM. Employing this rich cellular and transcriptomic resource, we identified lineage-specific catabolic signaling mechanisms that drive divergent cell behavior and therapeutic sensitivities that, in turn, demonstrate the power of employing lineage-specific stem cell models to dissect multi-system diseases.Website DOI
