Long-term organoid culture of a small intestinal neuroendocrine tumor

Front Endocrinol (Lausanne). 2023 Apr 4:14:999792. doi: 10.3389/fendo.2023.999792. eCollection 2023.

Abstract

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and highly heterogeneous neoplasms whose incidence has markedly increased over the last decades. A grading system based on the tumor cells' proliferation index predicts high-risk for G3 NETs. However, low-to-intermediate grade (G1/G2) NETs have an unpredictable clinical course that varies from indolent to highly malignant. Cultures of human cancer cells enable to perform functional perturbation analyses that are instrumental to enhance our understanding of cancer biology. To date, no tractable and reliable long-term culture of G1/G2 NET has been reported to permit disease modeling and pharmacological screens. Here, we report of the first long-term culture of a G2 metastatic small intestinal NET that preserves the main genetic drivers of the tumor and retains expression patterns of the endocrine cell lineage. Replicating the tissue, this long-term culture showed a low proliferation index, and yet it could be propagated continuously without dramatic changes in the karyotype. The model was readily available for pharmacological screens using targeted agents and as expected, showed low tumorigenic capacity in vivo. Overall, this is the first long-term culture of NETs to faithfully recapitulate many aspects of the original neuroendocrine tumor.

Keywords: 3D culture; neuroendocrine tumor; organoids; preclinical model; small intestinal tumor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Intestinal Neoplasms
  • Ki-67 Antigen / metabolism
  • Neoplasm Grading
  • Neuroendocrine Tumors* / pathology
  • Pancreatic Neoplasms
  • Prognosis
  • Receptor Protein-Tyrosine Kinases
  • Stomach Neoplasms

Substances

  • Ki-67 Antigen
  • Receptor Protein-Tyrosine Kinases

Supplementary concepts

  • Gastro-enteropancreatic neuroendocrine tumor

Grants and funding

VC is supported by AIRC (grant n 18178). VC is also supported by the EU (MSCA project PRECODE, grant No: 861196). VC and AS are also supported by the National Cancer Institute (NCI, HHSN26100008). AS is supported by AIRC IG (26343). SD’A was supported by AIRC (24043). EF is supported by AIRC (25286). PD has been supported by the Fondazione Nadia Valsecchi Onlus and partially by the Fondazione Umberto Veronesi. The funding agencies had no role in the collection, analysis, and interpretation of data or in the writing of the manuscript.