Objective Highly malignant pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant immunosuppressive and fibrotic tumour microenvironment (TME). Future therapeutic attempts will therefore demand the targeting of tumours and stromal compartments in order to be effective. Here we investigate whether dual specificity and tyrosine phosphorylation-regulated kinase 1B (DYRK1B) fulfil these criteria and represent a promising anticancer target in PDAC. Design We used transplantation and autochthonous mouse models of PDAC with either genetic Dyrk1b loss or pharmacological DYRK1B inhibition, respectively. Mechanistic interactions between tumour cells and macrophages were studied in direct or indirect co-culture experiments. Histological analyses used tissue microarrays from patients with PDAC. Additional methodological approaches included bulk mRNA sequencing (transcriptomics) and proteomics (secretomics). Results We found that DYRK1B is mainly expressed by pancreatic epithelial cancer cells and modulates the influx and activity of TME-associated macrophages through effects on the cancer cells themselves as well as through the tumour secretome. Mechanistically, genetic ablation or pharmacological inhibition of DYRK1B strongly attracts tumoricidal macrophages and, in addition, downregulates the phagocytosis checkpoint and ‘don’t eat me’ signal CD24 on cancer cells, resulting in enhanced tumour cell phagocytosis. Consequently, tumour cells lacking DYRK1B hardly expand in transplantation experiments, despite their rapid growth in culture. Furthermore, combining a small-molecule DYRK1B-directed therapy with mammalian target of rapamycin inhibition and conventional chemotherapy stalls the growth of established tumours and results in a significant extension of life span in a highly aggressive autochthonous model of PDAC. Conclusion In light of DYRK inhibitors currently entering clinical phase testing, our data thus provide a novel and clinically translatable approach targeting both the cancer cell compartment and its microenvironment. Data are available in a public, open access repository. Data availability: materials/methods data statement included. Datasets have been indicated in the clean manuscript version.

中文翻译：

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DYRK1B 阻断促进胰腺癌中杀瘤巨噬细胞活性


目的 高度恶性胰腺导管腺癌 （PDAC） 的特征是丰富的免疫抑制和纤维化肿瘤微环境 （TME）。因此，未来的治疗尝试将需要靶向肿瘤和基质隔室才能有效。在这里，我们研究了双重特异性和酪氨酸磷酸化调节激酶 1B （DYRK1B） 是否满足这些标准，并代表了 PDAC 中一个有前途的抗癌靶点。设计 我们分别使用了遗传性 Dyrk1b 缺失或药理学 DYRK1B 抑制的 PDAC 移植和本土小鼠模型。在直接或间接共培养实验中研究了肿瘤细胞和巨噬细胞之间的机制相互作用。组织学分析使用了 PDAC 患者的组织微阵列。其他方法学方法包括大量 mRNA 测序 （转录组学） 和蛋白质组学 （分泌组学）。结果 我们发现 DYRK1B 主要由胰腺上皮癌细胞表达，并通过对癌细胞本身以及肿瘤分泌组的影响来调节 TME 相关巨噬细胞的流入和活性。从机制上讲，DYRK1B 的基因消融或药理抑制强烈吸引杀瘤巨噬细胞，此外，下调癌细胞上的吞噬检查点和“不要吃我”信号 CD24，导致肿瘤细胞吞噬作用增强。因此，缺乏 DYRK1B 的肿瘤细胞尽管在培养物中生长迅速，但在移植实验中几乎不会扩增。 此外，将小分子 DYRK1B 定向疗法与哺乳动物雷帕霉素抑制靶点和常规化疗相结合，可延缓已建立肿瘤的生长，并在高度侵袭性的 PDAC 本土模型中显着延长寿命。结论鉴于目前进入临床阶段测试的 DYRK 抑制剂，我们的数据因此提供了一种针对癌细胞区室及其微环境的新型且临床可转化的方法。数据在公共、开放访问存储库中可用。数据可用性：包括材料/方法数据声明。数据集已在干净的手稿版本中标明。