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Three-Dimensional Primary Cell Culture: A Novel Preclinical Model for Pancreatic Neuroendocrine Tumors
Simon Leonhard April-Monn1,1, Tabea Wiedmer1,2, Magdalena Skowronska1
1Institute of Pathology, University of Bern, Bern, Switzerland.
Abstract:
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 samples. We believe that the presented human PanNET screening platform is suitable for personalized drug testing in a larger patient cohort, and a broader application will help in identifying novel markers predicting treatment response and in refining PanNET therapy.
Insights
Developing a novel 3D culture model for pancreatic neuroendocrine tumors (PanNETs) allows for personalized drug screening. This preclinical model shows varying patient responses to therapies, aiding future treatment selection.
Area of Science:
- Oncology
- Translational Research
- Biomedical Engineering
Background:
- Molecular mechanisms of pancreatic neuroendocrine tumors (PanNETs) and their progression remain poorly understood.
- Current PanNET therapies have limited efficacy, and patient stratification for personalized treatment is not yet feasible due to a lack of predictive markers.
- Rarity, heterogeneity, and insufficient preclinical models hinder PanNET research and therapeutic development.
Purpose of the Study:
- To establish a novel in vitro 3-dimensional (3-D) human primary PanNET culture system for personalized therapy selection.
- To present a screening platform for multicenter sample collection and drug screening in 3-D primary PanNET cell cultures.
- To demonstrate the utility of this model in evaluating patient-specific responses to existing PanNET therapies.
Main Methods:
- Isolation and in vitro culture of primary PanNET cells to form 3-D islet-like tumoroids.
- Assessment of tumoroid neuroendocrine phenotype and viability over time (at least 2 weeks).
- Screening of islet-like tumoroids with clinically approved PanNET therapies (sunitinib, everolimus, temozolomide) in a proof-of-concept study.
Main Results:
- Primary PanNET cells successfully formed viable islet-like tumoroids in vitro with an 86% success rate.
- Tumoroids retained their neuroendocrine phenotype and viability for over two weeks.
- Significant variations in treatment response to sunitinib, everolimus, and temozolomide were observed among different patient-derived tumoroids.
Conclusions:
- The developed 3-D human primary PanNET culture system serves as a viable preclinical model for personalized drug testing.
- This platform facilitates the identification of novel predictive markers for treatment response in PanNET patients.
- Broader application of this screening platform can refine therapeutic strategies and improve patient stratification for PanNET treatment.
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