Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites
Dayton, Talya L; Alcala, Nicolas; Moonen, Laura; den Hartigh, Lisanne; Geurts, Veerle; 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; Borel Rinkes, Inne H M; 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
(2023) Cancer Cell, volume 41, issue 12, pp. 2083 - 2099.e9
(Article)
Abstract
Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Treatment options for patients with NENs are limited, in part due to lack of accurate models. We establish patient-derived tumor organoids (PDTOs) from pulmonary NETs and derive PDTOs from an understudied subtype of NEC, large cell
... read more
neuroendocrine carcinoma (LCNEC), arising from multiple body sites. PDTOs maintain the gene expression patterns, intra-tumoral heterogeneity, and evolutionary processes of parental tumors. Through hypothesis-driven drug sensitivity analyses, we identify ASCL1 as a potential biomarker for response of LCNEC to treatment with BCL-2 inhibitors. Additionally, we discover a dependency on EGF in pulmonary NET PDTOs. Consistent with these findings, we find that, in an independent cohort, approximately 50% of pulmonary NETs express EGFR. This study identifies an actionable vulnerability for a subset of pulmonary NETs, emphasizing the utility of these PDTO models.
show less
Download/Full Text
Keywords: biomarker, cancer, cell neuroendocrine carcinoma, genomics, growth factor depenencies, intra-tumor heterogeneity, lung cancer, neuroendocrine tumorlarge, organoids, tumor evolution, Oncology, Cancer Research
ISSN: 1535-6108
Publisher: Cell Press
Note: Publisher Copyright: © 2023 The Authors
(Peer reviewed)