Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development.

Statement of significance

PDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors.

胰腺导管腺癌 (PDAC) 是一种侵袭性癌症，在临床上仍难以控制。在这里，我们采用基于 RNAi 的体内功能基因组学平台来确定一组患者衍生的 PDAC 模型的表观遗传漏洞。通过这一点，我们将蛋白质精氨酸甲基转移酶 1 (PRMT1) 确定为 PDAC 维护所需的关键依赖性。遗传和药理学研究验证了 PRMT1 在维持 PDAC 生长中的作用。从机制上讲，使用蛋白质组学和转录组学分析，我们证明不对称精氨酸甲基化的全局抑制会损害 RNA 代谢，包括 RNA 剪接、选择性多聚腺苷酸化和转录终止。这触发了参与 DNA 损伤反应的多种途径的强烈下调，从而促进基因组不稳定性并抑制肿瘤生长。总之，我们的数据支持 PRMT1 作为 PDAC 中一个引人注目的目标，并为未来的治疗发展提供基于机制的转化策略。

重要性声明

PDAC 是一种高度致命的癌症，治疗选择有限。本研究确定并表征了 PRMT1 依赖的 RNA 代谢调节和 PDAC 肿瘤生长所需的关键细胞过程的协调，为 PRMT1 抑制剂定义了基于机制的转化假设。