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Published on: October 24, 2019
An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping
Kenta Kawasaki1, Kohta Toshimitsu1, Mami Matano2
1Department of Organoid Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Abstract:
Gastroenteropancreatic (GEP) neuroendocrine neoplasm (NEN) that consists of neuroendocrine tumor and neuroendocrine carcinoma (NEC) is a lethal but under-investigated disease owing to its rarity. To fill the scarcity of clinically relevant models of GEP-NEN, we here established 25 lines of NEN organoids and performed their comprehensive molecular characterization. GEP-NEN organoids recapitulated pathohistological and functional phenotypes of the original tumors. Whole-genome sequencing revealed frequent genetic alterations in TP53 and RB1 in GEP-NECs, and characteristic chromosome-wide loss of heterozygosity in GEP-NENs. Transcriptome analysis identified molecular subtypes that are distinguished by the expression of distinct transcription factors. GEP-NEN organoids gained independence from the stem cell niche irrespective of genetic mutations. Compound knockout of TP53 and RB1, together with overexpression of key transcription factors, conferred on the normal colonic epithelium phenotypes that are compatible with GEP-NEN biology. Altogether, our study not only provides genetic understanding of GEP-NEN, but also connects its genetics and biological phenotypes.
Insights
Researchers developed 25 neuroendocrine neoplasm (NEN) organoid models to study rare gastroenteropancreatic (GEP) neuroendocrine neoplasms. These models revealed key genetic alterations and molecular subtypes, advancing understanding of GEP-NEN biology.
Area of Science:
- Oncology
- Gastroenterology
- Genetics
Background:
- Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare, lethal, and under-investigated diseases.
- Clinically relevant models for studying GEP-NENs are scarce, hindering research progress.
Purpose of the Study:
- To establish and molecularly characterize novel GEP-NEN organoid models.
- To elucidate the genetic underpinnings and molecular subtypes of GEP-NENs.
- To connect the genetic landscape with the biological phenotypes of GEP-NENs.
Main Methods:
- Generation of 25 GEP-NEN organoid lines from patient tumors.
- Comprehensive molecular characterization including whole-genome sequencing and transcriptome analysis.
- Functional validation of organoid models and genetic manipulation experiments.
Main Results:
- GEP-NEN organoids accurately recapitulated the pathohistological and functional features of original tumors.
- Whole-genome sequencing identified frequent TP53 and RB1 mutations in GEP-neuroendocrine carcinomas (NECs) and chromosome-wide loss of heterozygosity in GEP-NENs.
- Transcriptome analysis revealed distinct molecular subtypes defined by transcription factor expression; organoids achieved stem cell niche independence.
Conclusions:
- The study provides valuable GEP-NEN organoid models for preclinical research.
- Identified key genetic drivers (TP53, RB1) and molecular subtypes of GEP-NENs.
- Established a link between genetic alterations, transcription factor profiles, and GEP-NEN biological phenotypes.
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