Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease and a major health problem in the United States. While the cytokine TGF-β has been implicated in PDAC development, it can exert both pro-tumorigenic and anti-tumorigenic effects that are highly context dependent and incompletely understood. Using three-dimensional (3D) cultures of Kras^G12D-expressing mouse pancreatic epithelial cells we demonstrated that while exposure to exogenous TGF-β induced growth arrest of the Kras^G12D cells, its subsequent removal allowed the cells to enter a hyper-proliferative, partially mesenchymal (PM), and progenitor-like state. This state was highly stable and was maintained by autocrine TGF-β signaling. While untreated Kras^G12D cells formed cystic lesions in vivo, PM cells formed ductal structures resembling human PanINs, suggesting that they had attained increased oncogenic potential. Supporting this hypothesis, we determined that the PM cells share salient molecular and phenotypic features with the quasi-mesenchymal/squamous subtype of human PDAC, which has the worst prognosis of any of the recently identified subtypes. Transient pulses of TGF-β have been observed during pancreatitis, a major risk factor for PDAC. Our data suggest that transient TGF-β exposure is sufficient to induce the acquisition of stable PDAC-associated phenotypes in pre-neoplastic Kras^G12D cells, providing novel molecular insight into the complex role of TGF-β in tumorigenesis.

中文翻译：

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肿瘤前胰腺细胞在短暂暴露于 TGF-β 后进入部分间质状态。


胰腺导管腺癌（PDAC）是一种致命的疾病，也是美国的一个主要健康问题。虽然细胞因子 TGF-β 与 PDAC 的发育有关，但它可以发挥促肿瘤和抗肿瘤作用，这些作用高度依赖于背景且不完全了解。使用表达 Kras ^G12D的小鼠胰腺上皮细胞的三维 (3D) 培养物，我们证明，虽然暴露于外源性 TGF-β 会诱导 Kras ^G12D细胞生长停滞，但随后的去除使细胞进入过度增殖、部分增殖状态。间充质（PM）和祖细胞样状态。这种状态高度稳定，并由自分泌 TGF-β 信号传导维持。虽然未经处理的 Kras ^G12D细胞在体内形成囊性病变，但 PM 细胞形成类似于人类 PanIN 的导管结构，表明它们的致癌潜力增加。为了支持这一假设，我们确定 PM 细胞与人类 PDAC 的准间充质/鳞状亚型具有显着的分子和表型特征，该亚型是最近发现的所有亚型中预后最差的。在胰腺炎期间观察到 TGF-β 的瞬时脉冲，这是 PDAC 的主要危险因素。我们的数据表明，短暂的 TGF-β 暴露足以诱导肿瘤前 Kras ^G12D细胞获得稳定的 PDAC 相关表型，为 TGF-β 在肿瘤发生中的复杂作用提供新的分子见解。