Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites
Abstract
SUMMARY Neuroendocrine 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 abstract Highlights PDTOs of pulmonary NETs and LCNEC were established PDTOs recapitulate intra-tumoral heterogeneity and evolution of parental tumors Drug assays reveal therapeutic vulnerabilities and biomarkers Pulmonary NET PDTOs are dependent on EGF
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BibTeX
@article{dayton2026druggable,
title = {{Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites}},
author = {Talya L. Dayton and Nicolas Alcala and Laura Moonen and Lisanne Den Hartigh and Veerle Geurts and Lise Mangiante and Lisa Lap and Antonella F.M. Dost and Joep Beumer and Sonja Levy and Rachel S. Van Leeuwaarde and Wenzel M. Hackeng and Kris Samsom and Catherine Voegele and Alexandra Sexton-Oates and Harry Begthel and Jeroen Korving and Lisa Hillen and Lodewijk A.A. Brosens and Sylvie Lantuejoul and Sridevi Jaksani and Niels F.M. Kok and Koen J. Hartemink and Houke M. Klomp and Inne H.M. Borel Rinkes and Anne-Marie Dingemans and Gerlof D. Valk and Menno R. Vriens and Wieneke Buikhuisen and Jose van Den Berg and Margot Tesselaar and Jules Derks and Ernst Jan Speel and Matthieu Foll and Lynnette Fernández-Cuesta and Hans Clevers},
journal = {Cancer Cell},
year = {2026},
month = oct,
doi = {10.1016/j.ccell.2023.11.007},
url = {https://hal.science/hal-05842054v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites
AU - Talya L. Dayton
AU - Nicolas Alcala
AU - Laura Moonen
AU - Lisanne Den Hartigh
AU - Veerle Geurts
AU - Lise Mangiante
AU - Lisa Lap
AU - Antonella F.M. Dost
AU - Joep Beumer
AU - Sonja Levy
AU - Rachel S. Van Leeuwaarde
AU - Wenzel M. Hackeng
AU - Kris Samsom
AU - Catherine Voegele
AU - Alexandra Sexton-Oates
AU - Harry Begthel
AU - Jeroen Korving
AU - Lisa Hillen
AU - Lodewijk A.A. Brosens
AU - Sylvie Lantuejoul
AU - Sridevi Jaksani
AU - Niels F.M. Kok
AU - Koen J. Hartemink
AU - Houke M. Klomp
AU - Inne H.M. Borel Rinkes
AU - Anne-Marie Dingemans
AU - Gerlof D. Valk
AU - Menno R. Vriens
AU - Wieneke Buikhuisen
AU - Jose van Den Berg
AU - Margot Tesselaar
AU - Jules Derks
AU - Ernst Jan Speel
AU - Matthieu Foll
AU - Lynnette Fernández-Cuesta
AU - Hans Clevers
PY - 2026
DA - 2026/10/28
JO - Cancer Cell
DO - 10.1016/j.ccell.2023.11.007
UR - https://hal.science/hal-05842054v1
AB - SUMMARY Neuroendocrine 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 abstract Highlights PDTOs of pulmonary NETs and LCNEC were established PDTOs recapitulate intra-tumoral heterogeneity and evolution of parental tumors Drug assays reveal therapeutic vulnerabilities and biomarkers Pulmonary NET PDTOs are dependent on EGF
SN - 1535-6108
ER -