Cancer cells are in continuous communication with the surrounding microenvironment and this communication can affect tumor evolution. In this work, we show that phospholipase D2 (PLD2) was overexpressed in colon tumors and is secreted by cancer cells, inducing senescence in neighboring fibroblasts. This occurs through its lipase domain. Senescence induced by its product, phosphatidic acid, leads to a senescence-associated secretory phenotype (SASP) able to increase the stem properties of cancer cells. This increase in stemness occurs by Wnt pathway activacion. This closes a feedback loop in which senescence acts as a crosspoint for the generation of CSCs mediated by phospholipid metabolism. We also demonstrate the connexion of both phenomena in mouse models in vivo showing that a high PLD2 expression increased stemness and tumorigenesis. Thus, the patients with colon cancer show high levels of PLD2 and SASP factor genes expression correlating with Wnt pathway activation. Therefore, we demonstrate that tumor cell-secreted PLD2 contributes to tumor development by modifying the microenvironment, making it a possible therapeutic target for cancer treatment. This mechanism may also explain the high levels of Wnt pathway activation in colon cancer.

中文翻译：

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肿瘤细胞分泌的PLD通过衰老介导的与微环境的交流来增加肿瘤干性。

癌细胞与周围的微环境不断交流，这种交流会影响肿瘤的进化。在这项工作中，我们发现磷脂酶 D2 (PLD2) 在结肠肿瘤中过度表达并由癌细胞分泌，从而诱导邻近的成纤维细胞衰老。这是通过其脂肪酶结构域发生的。由其产物磷脂酸诱导的衰老导致衰老相关分泌表型 (SASP) 能够增加癌细胞的干细胞特性。这种干性增加是由 Wnt 通路激活引起的。这关闭了一个反馈回路，其中衰老充当由磷脂代谢介导的 CSC 生成的交叉点。我们还在体内小鼠模型中证明了这两种现象的联系，表明高 PLD2 表达增加了干性和肿瘤发生。因此，结肠癌患者显示出与 Wnt 通路激活相关的高水平 PLD2 和 SASP 因子基因表达。因此，我们证明肿瘤细胞分泌的PLD2通过改变微环境促进肿瘤发展，使其成为癌症治疗的可能治疗靶点。这种机制也可以解释结肠癌中 Wnt 通路的高水平激活。