Cancer cell heterogeneity is a major therapeutic challenge. Here, we identify that individual cells within cancer cell populations show significant heterogeneity in the levels of the stress-adaptive organelles, stress granules (SGs), and demonstrate that SG heterogeneity is dictated by cell-cycle state. Specifically, SG-formation is distinctively heightened in cells in G2-phase due to the interplay between a non-apoptotic function of Caspase 3 and calcium-dependent phospholipase A2 (cPLA2)-mediated production of the SG-promoting molecule, 15-deoxy-delta-prostaglandin-J2 (15d-PGJ2). We demonstrate that in G1/S phase, Caspase 3 cleaves and inactivates cPLA2, whereas in G2-phase, Caspase 3 activity is suppressed, resulting in enhanced cPLA2 activity and 15d-PGJ2 upregulation. We show that cell-cycle-dependent SG heterogeneity is a property of pancreatic ductal adenocarcinoma (PDAC) and targeting G2-SGs by inhibiting cPLA2 sensitizes PDAC to G2-arrest-inducing chemotherapeutics. Our findings highlight cell-cycle-dependent SG formation as a fundamental property of SGs, a key aspect of cancer heterogeneity, and a target for cancer treatment.

中文翻译：

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胞质磷脂酶 A2 决定应激颗粒的细胞间异质性和化疗反应

癌细胞异质性是一项重大的治疗挑战。在这里，我们确定癌细胞群中的单个细胞在应激适应细胞器、应激颗粒 （SG） 的水平上表现出显着的异质性，并证明 SG 异质性是由细胞周期状态决定的。具体而言，由于 Caspase 3 的非凋亡功能与钙依赖性磷脂酶 A2 （cPLA2） 介导的 SG 促进分子 15-脱氧-δ-前列腺素-J2 （15d-PGJ2） 的产生之间的相互作用，SG 形成在 G2 期细胞中显著增强。我们证明，在 G1/S 期，Caspase 3 裂解并使 cPLA2 失活，而在 G2 期，Caspase 3 活性受到抑制，导致 cPLA2 活性增强和 15d-PGJ2 上调。我们表明细胞周期依赖性 SG 异质性是胰腺导管腺癌 （PDAC） 的一种特性，通过抑制 cPLA2 靶向 G2-SGs 使 PDAC 对 G2 阻滞诱导化疗药物敏感。我们的研究结果强调细胞周期依赖性 SG 的形成是 SGs 的基本特性，是癌症异质性的关键方面，也是癌症治疗的靶点。