Ductal and acinar pancreatic organoids are promising models for the study of pancreatic diseases. Genome sequencing studies have revealed that mutations in a G-protein (GNASR201C) are exclusively observed in intraductal papillary mucinous neoplasms (IPMNs). The biological mechanisms by which GNASR201C affects the ductal and acinar exocrine pancreas are unclear. Here, we use human stem-cell-derived pancreatic ductal and acinar organoids and demonstrate that GNASR201C was more effective in inducing proliferation in ductal organoids compared to acinar organoids. Surprisingly, GNASR201C-induced cell proliferation was protein kinase A (PKA)-independent in ductal organoids and an immortalized ductal epithelial cell line. Co-expression of oncogenic KRASG12V and GNASR201C retained PKA-independence in ductal organoids to stimulate cell proliferation. Thus, we identify cell lineage-specific roles for PKA signaling in GNASR201C-driven cell proliferation in pre-cancerous lesions and report the development of a human pancreatic ductal organoid model system to investigate mechanisms regulating GNASR201C-induced IPMNs. Implications: The study identifies an opportunity to discover a PKA-independent pathway downstream of oncogene GNAS for managing IPMN lesions and their progression to PDAC.

中文翻译：

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致癌 GNAS 使用 PKA 依赖性和独立机制诱导人胰腺导管和腺泡类器官的细胞增殖

导管和腺泡胰腺类器官是研究胰腺疾病的有前途的模型。基因组测序研究表明，G 蛋白 (GNASR201C) 突变仅在导管内乳头状粘液性肿瘤 (IPMN) 中观察到。GNASR201C 影响导管和腺泡外分泌胰腺的生物学机制尚不清楚。在这里，我们使用人类干细胞来源的胰腺导管和腺泡类器官，并证明与腺泡类器官相比，GNASR201C 在诱导导管类器官增殖方面更有效。令人惊讶的是，GNASR201C 诱导的细胞增殖在导管类器官和永生化导管上皮细胞系中不依赖于蛋白激酶 A (PKA)。致癌 KRASG12V 和 GNASR201C 的共表达在导管类器官中保留了 PKA 独立性，以刺激细胞增殖。因此，我们确定了 PKA 信号在癌前病变中 GNASR201C 驱动的细胞增殖中的细胞谱系特异性作用，并报告了人类胰腺导管类器官模型系统的开发，以研究调节 GNASR201C 诱导的 IPMN 的机制。意义：该研究发现了一个机会，可以发现癌基因 GNAS 下游的 PKA 独立通路，用于管理 IPMN 病变及其进展为 PDAC。