Abstract：
Gastric neuroendocrine carcinomas (G-NEC) are aggressive malignancies with poorly understood biology and a lack of disease models. Here, we use genome sequencing to characterize the genomic landscapes of human G-NEC and its histologic variants. We identify global and subtype-specific alterations and expose hitherto unappreciated gains of MYC family members in a large part of cases. Genetic engineering and lineage tracing in mice delineate a model of G-NEC evolution, which defines MYC as a critical driver and positions the cancer cell of origin to the neuroendocrine compartment. MYC-driven tumors have pronounced metastatic competence and display defined signaling addictions, as revealed by large-scale genetic and pharmacologic screening of cell lines and organoid resources. We create global maps of G-NEC dependencies, highlight critical vulnerabilities, and validate therapeutic targets, including candidates for clinical drug repurposing. Our study gives comprehensive insights into G-NEC biology.
摘要：
胃神经内分泌癌（G-NEC）是侵袭性恶性肿瘤，对生物学了解甚少，缺乏疾病模型。这里,我们使用基因组测序来表征人类G-NEC及其组织学变异的基因组景观.我们确定了全局和亚型特异性的改变，并在很大一部分病例中揭示了迄今为止MYC家族成员尚未得到重视的收益。小鼠的基因工程和谱系追踪描绘了G-NEC进化的模型，将MYC定义为关键驱动因素，并将起源的癌细胞定位到神经内分泌室。MYC驱动的肿瘤具有明显的转移能力，并显示明确的信号成瘾，细胞系和类器官资源的大规模遗传和药理学筛选揭示了这一点。我们创建了G-NEC依赖关系的全球地图，突出关键漏洞，并验证治疗目标，包括临床药物再利用的候选人。我们的研究提供了对G-NEC生物学的全面见解。
