Patient derived tumoroids of high grade neuroendocrine neoplasms for more personalized therapies

Simon L April-Monn; Philipp Kirchner; Katharina Detjen; Konstantin Bräutigam; Mafalda A Trippel; Tobias Grob; Cyril Statzer; Renaud S Maire; Attila Kollàr; Aziz Chouchane; Catarina A Kunze; David Horst; Martin C Sadowski; Jörg Schrader; Ilaria Marinoni; Bertram Wiedenmann; Aurel Perren

doi:10.1038/s41698-024-00549-2

Patient derived tumoroids of high grade neuroendocrine neoplasms for more personalized therapies

NPJ Precis Oncol. 2024 Mar 1;8(1):59. doi: 10.1038/s41698-024-00549-2.

Authors

Simon L April-Monn^#^{1

2}, Philipp Kirchner^#¹, Katharina Detjen³, Konstantin Bräutigam¹, Mafalda A Trippel¹, Tobias Grob¹, Cyril Statzer⁴, Renaud S Maire¹, Attila Kollàr⁵, Aziz Chouchane¹, Catarina A Kunze⁶, David Horst⁶, Martin C Sadowski¹, Jörg Schrader⁷, Ilaria Marinoni^{1

8}, Bertram Wiedenmann³, Aurel Perren^{9

10}

Affiliations

¹ Institute of Tissue Medicine and Pathology, University of Bern, 3008, Bern, Switzerland.
² Graduate School for Cellular and Biomedical Sciences, University of Bern, 3008, Bern, Switzerland.
³ Charité-Universitaetsmedizin Berlin, Corporate Member of Freie Universitaet Berlin and Humboldt-Universitaet zu Berlin, Hepatology and Gastroenterology, Berlin, Germany.
⁴ Department of Health Sciences and Technology, Eidgenoessische Technische Hochschule Zuerich, Schwerzenbach-Zuerich, 8603, Switzerland.
⁵ Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse, CH-3010, Bern, Switzerland.
⁶ Institute of Pathology, Charité Universitaetsmedizin Berlin, Rudolf-Virchow-Haus, Berlin, Germany.
⁷ Department of Medicine, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany.
⁸ Bern Center for Precision Medicine, University & University Hospital of Bern, 3008, Bern, Switzerland.
⁹ Institute of Tissue Medicine and Pathology, University of Bern, 3008, Bern, Switzerland. aurel.perren@unibe.ch.
¹⁰ Bern Center for Precision Medicine, University & University Hospital of Bern, 3008, Bern, Switzerland. aurel.perren@unibe.ch.

^# Contributed equally.

Abstract

There are no therapeutic predictive biomarkers or representative preclinical models for high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), a highly aggressive, fatal, and heterogeneous malignancy. We established patient-derived (PD) tumoroids from biobanked tissue samples of advanced high-grade GEP-NEN patients and applied this model for targeted rapid ex vivo pharmacotyping, next-generation sequencing, and perturbational profiling. We used tissue-matched PD tumoroids to profile individual patients, compared ex vivo drug response to patients' clinical response to chemotherapy, and investigated treatment-induced adaptive stress responses.PD tumoroids recapitulated biological key features of high-grade GEP-NEN and mimicked clinical response to cisplatin and temozolomide ex vivo. When we investigated treatment-induced adaptive stress responses in PD tumoroids in silico, we discovered and functionally validated Lysine demethylase 5 A and interferon-beta, which act synergistically in combination with cisplatin. Since ex vivo drug response in PD tumoroids matched clinical patient responses to standard-of-care chemotherapeutics for GEP-NEN, our rapid and functional precision oncology approach could expand personalized therapeutic options for patients with advanced high-grade GEP-NEN.