Bulk 3-prime RNA-sequencing of macrodissected neuroendocrine and exocrine tumor components of FFPE-embedded mouse gastric neuroendocrine carcinomas. undefined

Gastric neuroendocrine carcinomas (G-NEC) are aggressive malignancies with poorly understood biology and a lack of disease models. Here, we describe molecular and cellular hallmarks of G-NEC evolution and devise new avenues for its therapy. Using whole-genome sequencing, we 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 two-thirds of cases. Genetic engineering and lineage tracing in mice delineates an integrated cellular and molecular 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 screens. We created global maps of G-NEC dependencies, highlight critical vulnerabilities and validate across species new therapeutic targets, including candidates for immediate clinical drug repurposing.

胃神经内分泌癌（Gastric neuroendocrine carcinomas, G-NEC）是一类侵袭性极强的恶性肿瘤，其生物学特性尚未明确，且缺乏相关疾病模型。本研究阐明了胃神经内分泌癌发生发展的分子与细胞特征，并为其治疗开辟了全新方向。通过全基因组测序，本研究解析了人类胃神经内分泌癌及其组织学亚型的基因组图谱，鉴定出全局性及亚型特异性的基因组改变，并揭示了此前未被重视的、在三分之二病例中检出的MYC家族基因拷贝数扩增现象。通过小鼠体内的基因工程操作与谱系示踪技术，本研究构建了胃神经内分泌癌发生发展的整合性细胞与分子模型，明确了MYC作为关键驱动基因的作用，并将肿瘤起源细胞定位于神经内分泌细胞区室。MYC驱动的肿瘤具有显著的转移能力，并表现出明确的信号通路成瘾特性，这一结论通过大规模遗传与药物筛选实验得以证实。本研究绘制了胃神经内分泌癌的全局依赖基因图谱，明确了其关键易感靶点，并通过跨物种实验验证了全新的治疗靶点，包括可立即开展临床药物重定位的候选靶点。