Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China; Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.
Cancer Lett. 2024 Nov 28;605:217289. doi: 10.1016/j.canlet.2024.217289. Epub 2024 Oct 9.
Pancreatic cancer is distinguished by an immunosuppressive tumor microenvironment (TME) that facilitates cancer progression. The assembly of the TME involves numerous contributing factors. Migrasomes, recently identified as cellular organelles in migrating cells, play a pivotal role in intercellular signaling. However, research into their involvement in cancers remains nascent. Thus far, whether pancreatic cancer cells generate migrasomes and their potential role in TME formation remains unexplored. In this study, it was found that both murine and human pancreatic cancer cells could indeed generate migrasomes, termed pancreatic cancer cell-derived migrasomes (PCDMs), which actively promote cancer progression. Moreover, utilizing chemokine antibody arrays and quantitative mass spectrometry analysis, we observed significant differences between the chemokines, cytokines, and proteins present in PCDMs compared to their originating cell bodies. Notably, PCDMs exhibited an enrichment of immunosuppression-inducing factors. Furthermore, macrophages could directly uptake PCDMs, leading to the expression of high levels of M2-like markers and secretion of tumor-promoting factors. PCDM-induced macrophages played a pivotal role in inhibiting T cell proliferation and activation partially through ARG-1. In summary, this study provides compelling evidence that pancreatic cancer cells generate migrasomes, which play a crucial role in promoting tumor progression by contributing to an immunosuppressive TME. The exploration of migrasomes as a therapeutic target could pave the way for the development of tailored immunotherapies for pancreatic cancer.
胰腺癌的特点是免疫抑制性肿瘤微环境（TME）促进癌症进展。TME 的组装涉及许多促成因素。迁移小体是最近在迁移细胞中发现的细胞细胞器，在细胞间信号传递中发挥关键作用。然而，关于它们在癌症中的作用的研究仍处于起步阶段。到目前为止，尚不清楚胰腺癌细胞是否会产生迁移小体以及它们在 TME 形成中的潜在作用。在这项研究中，发现鼠和人胰腺癌细胞确实可以产生迁移小体，称为胰腺癌细胞衍生的迁移小体（PCDM），它们积极促进癌症进展。此外，利用趋化因子抗体阵列和定量质谱分析，我们观察到 PCDM 中存在的趋化因子、细胞因子和蛋白质与它们的起源细胞体之间存在显著差异。值得注意的是，PCDM 表现出丰富的免疫抑制诱导因子。此外，巨噬细胞可以直接摄取 PCDM，导致高水平的 M2 样标志物的表达和促进肿瘤的因子的分泌。PCDM 诱导的巨噬细胞在抑制 T 细胞增殖和激活方面发挥了关键作用，部分是通过 ARG-1。总之，这项研究提供了令人信服的证据，表明胰腺癌细胞产生迁移小体，这些迁移小体通过促进免疫抑制性 TME 在促进肿瘤进展中发挥关键作用。迁移小体作为治疗靶点的探索可能为开发针对胰腺癌的定制免疫疗法铺平道路。
