小肠神经内分泌肿瘤 (SI-NETs) 是可能源于肠组织素 (EC) 细胞的血清素分泌良性神经内分泌肿瘤。然而，EC 细胞源性的肿瘤形成还不够清楚。在这里，我们通过使用色氨酸羟化酶 1 (TPH1) Cre-ERT2 驱动的 RB1fl Trp53fl MycLSL (RPM) 小鼠检测 EC 细胞中 Myc 的增强和 RB1 和 Trp53 功能的丧失是否导致 SI-NET。TPH1-Cre 诱导的 Myc 增强和 RB1 和 Trp53 功能的丧失导致胰腺、肺、肠道神经元和大脑内分泌或神经肿瘤。祖孙追踪表明这些肿瘤的细胞起源是这些器官中表达 TPH1 的神经内分泌细胞、神经元或它们的先体细胞。然而，尽管 TPH1 最高表达于小肠 EC 细胞中，但我们观察到没有 EC 细胞肿瘤的发生。相反，肠道上皮细胞来源的肿瘤仅为非内分泌类癌，表明 EC 细胞向肠干细胞 (ISCs) 的去分化是一种细胞机制。此外，外体器官研究表明，Rb1 和 Trp53 的功能丧失加速了易受 MycT58A 活性启动后凋亡的 EC 细胞的去分化，表明逃脱细胞死亡的罕见去分化细胞继而发展为腺癌。祖孙追踪表明，与其他器官中的神经内分泌或神经元细胞相比，小肠中的 EC 细胞寿命短。相反，EC 细胞来源的 ISCs 持久并处于活跃状态，因此易受转化影响。这些结果表明，EC 细胞的组织和细胞特性，如快速的细胞变换和稳态去分化，影响了遗传变异引起的肿瘤形成的命运和速率，导致极少量的腺癌的发生。这为 EC 细胞来源的肿瘤形成提供了重要的见解。新的和值得注意的是，小肠神经内分泌肿瘤可能源于肠组织素细胞，是小肠中最常见的恶性肿瘤，其次是腺癌。然而，这些肿瘤类型的肿瘤形成还不十分清楚。本研究的祖孙追踪研究表明，EC 细胞的组织和细胞特性，如快速的细胞变换和稳态去分化，影响了遗传变异引起的肿瘤形成的命运和速率，指向一种罕见的腺癌的发生。

Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting well-differentiated neuroendocrine tumors of putative enterochromaffin (EC) cell origin. However, EC cell-derived tumorigenesis remains poorly understood. Here, we examined whether the gain of Myc and the loss of RB1 and Trp53 function in EC cells result in SI-NET using tryptophan hydroxylase 1 (TPH1) Cre-ERT2-driven RB1fl Trp53fl MycLSL (RPM) mice. TPH1-Cre-induced gain of Myc and loss of RB1 and Trp53 function resulted in endocrine or neuronal tumors in pancreas, lung, enteric neurons, and brain. Lineage tracing indicated that the cellular origin for these tumors was TPH1-expressing neuroendocrine, neuronal, or their precursor cells in these organs. However, despite that TPH1 is most highly expressed in EC cells of the small intestine, we observed no incidence of EC cell tumors. Instead, the tumor of epithelial cell origin in the intestine was exclusively nonendocrine adenocarcinoma, suggesting dedifferentiation of EC cells into intestinal stem cells (ISCs) as a cellular mechanism. Furthermore, ex vivo organoid studies indicated that loss of functions of Rb1 and Trp53 accelerated dedifferentiation of EC cells that were susceptible to apoptosis with expression of activated MycT58A, suggesting that the rare dedifferentiating cells escaping cell death went on to develop adenocarcinomas. Lineage tracing demonstrated that EC cells in the small intestine were short-lived compared with neuroendocrine or neuronal cells in other organs. In contrast, EC cell-derived ISCs were long-lasting and actively cycling and thus susceptible to transformation. These results suggest that tissue- and cell-specific properties of EC cells such as rapid cell turnover and homeostatic dedifferentiation, affect the fate and rate of tumorigenesis induced by genetic alterations and provide important insights into EC cell-derived tumorigenesis.NEW & NOTEWORTHY Small intestinal neuroendocrine tumors are of putative enterochromaffin (EC) cell origin and are the most common malignancy in the small intestine, followed by adenocarcinoma. However, the tumorigenesis of these tumor types remains poorly understood. The present lineage tracing studies showed that tissue- and cell-specific properties of EC cells such as rapid cell turnover and homeostatic dedifferentiation affect the fate and rate of tumorigenesis induced by genetic alterations toward a rare occurrence of adenocarcinoma.