Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites

  • Cancer Cell. 2023 Dec 11;41(12):2083-2099.e9. doi: 10.1016/j.ccell.2023.11.007.
Talya L Dayton  1 ,  Nicolas Alcala  2 ,  Laura Moonen  3 ,  Lisanne den Hartigh  4 ,  Veerle Geurts  4 ,  Lise Mangiante  2 ,  Lisa Lap  3 ,  Antonella F M Dost  5 ,  Joep Beumer  5 ,  Sonja Levy  6 ,  Rachel S van Leeuwaarde  7 ,  Wenzel M Hackeng  8 ,  Kris Samsom  9 ,  Catherine Voegele  2 ,  Alexandra Sexton-Oates  2 ,  Harry Begthel  4 ,  Jeroen Korving  4 ,  Lisa Hillen  3 ,  Lodewijk A A Brosens  8 ,  Sylvie Lantuejoul  10 ,  Sridevi Jaksani  11 ,  Niels F M Kok  12 ,  Koen J Hartemink  12 ,  Houke M Klomp  12 ,  Inne H M Borel Rinkes  13 ,  Anne-Marie Dingemans  14 ,  Gerlof D Valk  7 ,  Menno R Vriens  13 ,  Wieneke Buikhuisen  15 ,  José van den Berg  9 ,  Margot Tesselaar  6 ,  Jules Derks  16 ,  Ernst Jan Speel  3 ,  Matthieu Foll  2 ,  Lynnette Fernández-Cuesta  17 ,  Hans Clevers  18
Affiliations
  • 1. Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, 3584 CT Utrecht, the Netherlands; Oncode Institute, Hubrecht Institute, 3584 CT Utrecht, the Netherlands. Electronic address: [email protected].
  • 2. Rare Cancers Genomics Team (RCG), Genomic Epidemiology Branch (GEM), International Agency for Research on Cancer/World Health Organisation (IARC/WHO), 69007 Lyon, France.
  • 3. Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Centre, 6229 ER Maastricht, the Netherlands.
  • 4. Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, 3584 CT Utrecht, the Netherlands.
  • 5. Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, 3584 CT Utrecht, the Netherlands; Oncode Institute, Hubrecht Institute, 3584 CT Utrecht, the Netherlands.
  • 6. Department of Medical Oncology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
  • 7. Department of Endocrine Oncology, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
  • 8. Department of Pathology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, the Netherlands.
  • 9. Department of Pathology, Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
  • 10. Department of Biopathology, Pathology Research Platform- Synergie Lyon Cancer- CRCL, Centre Léon Bérard Unicancer, 69008 Lyon, France; Université Grenoble Alpes, Grenoble, France.
  • 11. Hubrecht Organoid Technology, Utrecht 3584 CM, the Netherlands.
  • 12. Department of Surgery, Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
  • 13. Department of Endocrine Surgical Oncology, University Medical Center Utrecht, Utrecht 3508 GA, the Netherlands.
  • 14. Department of Pulmonary Diseases, GROW School for Oncology and and Reproduction, Maastricht University Medical Centre, Maastricht, the Netherlands; Department of Pulmonary Medicine, Erasmus MC Cancer Institute, University Medical Center, Rotterdam 3015 GD, the Netherlands.
  • 15. Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
  • 16. Department of Pulmonary Diseases, GROW School for Oncology and and Reproduction, Maastricht University Medical Centre, Maastricht, the Netherlands.
  • 17. Rare Cancers Genomics Team (RCG), Genomic Epidemiology Branch (GEM), International Agency for Research on Cancer/World Health Organisation (IARC/WHO), 69007 Lyon, France. Electronic address: [email protected].
  • 18. Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, 3584 CT Utrecht, the Netherlands; Oncode Institute, Hubrecht Institute, 3584 CT Utrecht, the Netherlands. Electronic address: [email protected].
PMID: 38086335 DOI: 10.1016/j.ccell.2023.11.007
Abstract

Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Treatment options for patients with NENs are limited, in part due to lack of accurate models. We establish patient-derived tumor organoids (PDTOs) from pulmonary NETs and derive PDTOs from an understudied subtype of NEC, large cell neuroendocrine carcinoma (LCNEC), arising from multiple body sites. PDTOs maintain the gene expression patterns, intra-tumoral heterogeneity, and evolutionary processes of parental tumors. Through hypothesis-driven drug sensitivity analyses, we identify ASCL1 as a potential biomarker for response of LCNEC to treatment with Bcl-2 inhibitors. Additionally, we discover a dependency on EGF in pulmonary NET PDTOs. Consistent with these findings, we find that, in an independent cohort, approximately 50% of pulmonary NETs express EGFR. This study identifies an actionable vulnerability for a subset of pulmonary NETs, emphasizing the utility of these PDTO models.

Keywords
biomarker; cancer; cell neuroendocrine carcinoma; genomics; growth factor depenencies; intra-tumor heterogeneity; lung cancer; neuroendocrine tumorlarge; organoids; tumor evolution.
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