Druggable Growth Dependencies and Tumor Evolution Analysis in Patient-Derived Organoids of Neuroendocrine Cancer
Author:
Dayton Talya L.ORCID, Alcala Nicolas, Moonen Laura, den Hartigh Lisanne, Mangiante Lise, Lap Lisa, Dost Antonella F. M., Beumer Joep, Levy Sonja, van Leeuwaarde Rachel S., Hackeng Wenzel M., Samsom Kris, Voegele Catherine, Sexton-Oates Alexandra, Begthel Harry, Korving Jeroen, Hillen Lisa, Brosens Lodewijk A. A., Lantuejoul Sylvie, Jaksani Sridevi, Kok Niels F.M., Hartemink Koen J., Klomp Houke M., Rinkes Inne H.M. Borel, Dingemans Anne-Marie, Valk Gerlof D., Vriens Menno R., Buikhuisen Wieneke, van den Berg José, Tesselaar Margot, Derks Jules, Speel Ernst Jan, Foll Matthieu, Fernández-Cuesta Lynnette, Clevers Hans
Abstract
SUMMARYNeuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors and poorly-differentiated carcinomas. Treatment options for patients with NENs are limited, in part due to lack of accurate models. To address this need we established the first patient-derived tumor organoids (PDTOs) from pulmonary neuroendocrine tumors and derived PDTOs from an understudied NEN subtype, large cell neuroendocrine carcinoma (LCNEC). PDTOs maintain the gene expression patterns, intra-tumoral heterogeneity, and evolutionary processes of parental tumors. Through drug sensitivity analyses, we uncover therapeutic sensitivities to an inhibitor of NAD salvage biosynthesis and to an inhibitor of BCL-2. Finally, we identify a dependency on EGF in pulmonary neuroendocrine tumor PDTOs. Consistent with these findings, analysis of an independent cohort showed that approximately 50% of pulmonary neuroendocrine tumors expressed EGFR. This study identifies a potentially actionable vulnerability for a subset of NENs, and further highlights the utility of these novel PDTO models for the study of NENs.Graphical abstractHighlightsPDTOs of pulmonary NETs and LCNEC were establishedPDTOs recapitulate intra-tumoral heterogeneity and evolution of parental tumorsDrug assays reveal therapeutic vulnerabilities and biomarkersPulmonary NET PDTOs are dependent on EGF
Publisher
Cold Spring Harbor Laboratory
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