Pancreatic ductal adenocarcinoma (PDA), a leading cause of cancer-related death in the United States, has a high metastatic rate, and is associated with persistent immune suppression. AXL, a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family, is a driver of metastasis and immune suppression in multiple cancer types. Here we use single-cell RNA-sequencing to reveal that AXL is expressed highly in tumor cells that have a mesenchymal-like phenotype and that AXL expression correlates with classic markers of epithelial-to-mesenchymal transition. We demonstrate that AXL deficiency extends survival, reduces primary and metastatic burden, and enhances sensitivity to gemcitabine in an autochthonous model of PDA. PDA in AXL-deficient mice displayed a more differentiated histology, higher nucleoside transporter expression, and a more active immune microenvironment compared with PDA in wild-type mice. Finally, we demonstrate that AXL-positive poorly differentiated tumor cells are critical for PDA progression and metastasis, emphasizing the potential of AXL as a therapeutic target in PDA. Implications: These studies implicate AXL as a marker of undifferentiated PDA cells and a target for therapy. This article is featured in Highlights of This Issue, [p. 1249][1] [1]: /lookup/volpage/19/1249?iss=8

中文翻译：

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AXL 是胰腺癌细胞可塑性和促进转移的关键因素

胰腺导管腺癌 (PDA) 是美国癌症相关死亡的主要原因，具有高转移率，并与持续的免疫抑制有关。AXL 是 TAM（TYRO3、AXL、MERTK）受体酪氨酸激酶家族的成员，是多种癌症类型转移和免疫抑制的驱动因素。在这里，我们使用单细胞 RNA 测序来揭示 AXL 在具有间充质样表型的肿瘤细胞中高表达，并且 AXL 表达与上皮-间质转化的经典标志物相关。我们证明了 AXL 缺乏延长了生存期，减少了原发性和转移性负担，并提高了 PDA 本土模型中对吉西他滨的敏感性。AXL 缺陷小鼠的 PDA 表现出更分化的组织学，更高的核苷转运蛋白表达，与野生型小鼠的PDA相比，免疫微环境更活跃。最后，我们证明 AXL 阳性低分化肿瘤细胞对 PDA 进展和转移至关重要，强调了 AXL 作为 PDA 治疗靶点的潜力。启示：这些研究表明 AXL 作为未分化 PDA 细胞的标志物和治疗靶点。这篇文章被收录在本期的亮点中，[p. 1249][1][1]：/lookup/volpage/19/1249?iss=8 这篇文章被收录在本期的亮点中，[p. 1249][1][1]：/lookup/volpage/19/1249?iss=8 这篇文章被收录在本期的亮点中，[p. 1249][1][1]：/lookup/volpage/19/1249?iss=8