Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a family of tumors that arise throughout the gastrointestinal tract. These tumors are heterogeneous, with complex clinical symptoms and tumor behaviors, and demonstrate rising incidence rates worldwide. In addition to their nature, GEP-NETs possess limited diagnostic and therapeutic options, which results in poor survival rates for patients with metastatic tumors. Given these findings, a further analysis of these tumors’ biology is needed to determine new therapeutic strategies. The tumor microenvironment (TME) consists of several residual cell populations and non-cellular components whose altered behavior creates a tumor-supportive niche. Studies from other cancers demonstrate the TME’s significance in tumor initiation, progression, and spread. In this review, we discuss efforts to characterize the TME in GEP-NETs. Preliminary studies of the immune system in GEP-NETs have led to several major clinical trials, with limited success. Efforts to target signaling crosstalk between cancer-associated fibroblasts, vascular endothelial cells, and tumor cells has led to major discoveries and multiple approved therapies. Finally, alterations to the extracellular matrix may lead towards an improved understanding of GEP-NET development, behavior, and improved detection methods. While research has rapidly expanded our knowledge within the last decade, further work is needed to bring our understanding of the GEP-NET TME in line with other rare cancers.

Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) are a rare subset of cancers with increasing incidence. Due to their slow growth and lack of targetable mutations, the identification of effective treatments remains limited. One reason behind this stagnation is the lack of applicable, accurate study models. One solution is patient tumor organoids (PTOs) that maintain tumor characteristics and can scale for high throughput assays. In this study, PTOs were generated from 35 tumors of pancreatic, small intestinal, and gastric origin, obtained from 17 patients. Important subtypes including hormone functional and MEN1 / VHL mutant GEP-NETs are represented, with each demonstrating growth in culture while maintaining GEP-NET immunohistochemistry and genomic characteristics. Half of G2/G3 tumors (10 of 20) could be cultured past passage 6, whereas G1 tumors ( n = 15) were capable of growth until passage 4. Therapeutic targeting of the PTOs displayed both tissue-origin and grade-based response to standard of care and investigational therapies while maintaining patient tumor sensitivity and resistance. Last, a successful PTO xenograft model was developed from one PTO line. This study describes GEP-NET organoid development that demonstrates feasibility for expansion, enabling their use for translational investigations.

Maria Chiara Siciliano, Dr, Giorgio Bertolazzi, Selina Glaser, Massimo Granai, Cosimo Lori, Roberto Boccacci, Dr, Srujana V. Yellapragada, Margherita Vannu