An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping
An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping
复制标题
DOI：
10.1016/j.cell.2020.10.023
复制
发表时间：
2020-11-25
期刊：
影响因子：
64.5
通讯作者：
Sato, Toshiro
中科院分区：
文献类型：
--
作者：
Kawasaki, Kenta;Toshimitsu, Kohta;Sato, Toshiro
胃肠胰腺肿瘤(GEP)是由神经内分泌肿瘤和神经内分泌癌(NEC)组成的一种少见的致死性疾病。为了填补GEP-NEN临床相关模型的不足，我们在这里建立了25个NEN有机化合物系，并对它们进行了全面的分子表征。GEP-NEN类器官概括了原始肿瘤的病理、组织学和功能表型。全基因组测序显示GEP-NECS的TP53和RB1基因突变频繁，GEP-NECS具有典型的全染色体杂合性丢失。转录组分析确定了通过不同转录因子的表达来区分的分子亚型。GEP-NEN类有机物获得了独立于干细胞生态位的能力，而不受基因突变的影响。TP53和RB1的复合敲除，加上关键转录因子的过度表达，赋予了与GEP-NEN生物学相容的正常结肠上皮表型。总之，我们的研究不仅提供了对GEP-Nen的遗传学理解，还将其遗传学和生物学表型联系起来。
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.