Three-Dimensional Primary Cell Culture: A Novel Preclinical Model for Pancreatic Neuroendocrine Tumors

作者：Simon April-Monn, Tabea Wiedmer, Magdalena Skowronska, Renaud Maire, Marco Schiavo Lena, Mafalda A. Trippel, Annunziata Di Domenico, Francesca Muffatti, Valentina Andreasi, Gabriele Capurso, Claudio Doglioni, Corina Kim‐Fuchs, Beat Gloor, Maria Chiara Zatelli, Stefano Partelli, Massimo Falconi, Aurel A. Perren, Ilaria Marinoni · 发表于：Neuroendocrinology · 年份：2020 · DOI：10.1159/000507669 · 被引用次数：59 · 研究领域：Neuroendocrine Tumor Research Advances、Pancreatic and Hepatic Oncology Research、Neuroblastoma Research and Treatments

Molecular mechanisms underlying the development and progression of pancreatic neuroendocrine tumors (PanNETs) are still insufficiently understood. Efficacy of currently approved PanNET therapies is limited. While novel treatment options are being developed, patient stratification permitting more personalized treatment selection in PanNET is yet not feasible since no predictive markers are established. The lack of representative in vitro and in vivo models as well as the rarity and heterogeneity of PanNET are prevailing reasons for this. In this study, we describe an in vitro 3-dimensional (3-D) human primary PanNET culture system as a novel preclinical model for more personalized therapy selection. We present a screening platform allowing multicenter sample collection and drug screening in 3-D cultures of human primary PanNET cells. We demonstrate that primary cells isolated from PanNET patients and cultured in vitro form islet-like tumoroids. Islet-like tumoroids retain a neuroendocrine phenotype and are viable for at least 2 weeks in culture with a high success rate (86%). Viability can be monitored continuously allowing for a per-well normalization. In a proof-of-concept study, islet-like tumoroids were screened with three clinically approved therapies for PanNET: sunitinib, everolimus and temozolomide. Islet-like tumoroids display varying in vitro response profiles to distinct therapeutic regimes. Treatment response of islet-like tumoroids differs also between patient sam...