Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers due to its aggressive and metastatic nature. PDA is characterized by a rich tumor stroma with abundant macrophages, fibroblasts, and collagen deposition that can represent up to 90% of the tumor mass. Activation of the tyrosine kinase receptor AXL and expression of its ligand growth arrest-specific protein 6 (Gas6) correlate with a poor prognosis and increased metastasis in pancreatic cancer patients. Gas6 is a multifunctional protein that can be secreted by several cell types and regulates multiple processes, including cancer cell plasticity, angiogenesis, and immune cell functions. However, the role of Gas6 in pancreatic cancer metastasis has not been fully investigated. In these studies we find that, in pancreatic tumors, Gas6 is mainly produced by tumor associated macrophages (TAMs) and cancer associated fibroblasts (CAFs) and that pharmacological blockade of Gas6 signaling partially reverses epithelial-to-mesenchymal transition (EMT) of tumor cells and supports NK cell activation, thereby inhibiting pancreatic cancer metastasis. Our data suggest that Gas6 simultaneously acts on both the tumor cells and the NK cells to support pancreatic cancer metastasis. This study supports the rationale for targeting Gas6 in pancreatic cancer and use of NK cells as a potential biomarker for response to anti-Gas6 therapy.

中文翻译：

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基质气体的阻断可改变癌细胞的可塑性、激活 NK 细胞并抑制胰腺癌转移。


胰腺导管腺癌（PDA）因其侵袭性和转移性而成为最致命的癌症之一。 PDA 的特点是肿瘤基质丰富，具有丰富的巨噬细胞、成纤维细胞和胶原沉积，可占肿瘤质量的 90%。酪氨酸激酶受体 AXL 的激活及其配体生长抑制特异性蛋白 6 (Gas6) 的表达与胰腺癌患者的不良预后和转移增加相关。 Gas6是一种多功能蛋白，可由多种细胞类型分泌并调节多种过程，包括癌细胞可塑性、血管生成和免疫细胞功能。然而，Gas6在胰腺癌转移中的作用尚未得到充分研究。在这些研究中，我们发现，在胰腺肿瘤中，Gas6 主要由肿瘤相关巨噬细胞 (TAM) 和癌症相关成纤维细胞 (CAF) 产生，药物阻断 Gas6 信号传导可部分逆转肿瘤细胞的上皮间质转化 (EMT)支持NK细胞活化，从而抑制胰腺癌转移。我们的数据表明 Gas6 同时作用于肿瘤细胞和 NK 细胞以支持胰腺癌转移。这项研究支持了在胰腺癌中靶向 Gas6 以及使用 NK 细胞作为抗 Gas6 疗法反应的潜在生物标志物的基本原理。