Alternative polyadenylation (APA) is strikingly dysregulated in many cancers. Although global APA dysregulation is frequently associated with poor prognosis, the importance of most individual APA events is controversial simply because few have been functionally studied. Here, we address this gap by developing a CRISPR-Cas9-based screen to manipulate endogenous polyadenylation and systematically quantify how APA events contribute to tumor growth in vivo. Our screen reveals individual APA events that control mouse melanoma growth in an immunocompetent host, with concordant associations in clinical human cancer. For example, forced Atg7 3′ UTR lengthening in mouse melanoma suppresses ATG7 protein levels, slows tumor growth, and improves host survival; similarly, in clinical human melanoma, a long ATG7 3′ UTR is associated with significantly prolonged patient survival. Overall, our study provides an easily adaptable means to functionally dissect APA in physiological systems and directly quantifies the contributions of recurrent APA events to tumorigenic phenotypes.

选择性聚腺苷酸化 （APA） 在许多癌症中明显失调。尽管整体 APA 失调通常与不良预后相关，但大多数个体 APA 事件的重要性存在争议，这仅仅是因为很少有功能研究。在这里，我们通过开发基于 CRISPR-Cas9 的筛选来操纵内源性多聚腺苷酸化并系统量化 APA 事件如何促进体内肿瘤生长，从而解决了这一差距。我们的筛选揭示了控制免疫功能正常宿主中小鼠黑色素瘤生长的单个 APA 事件，在临床人类癌症中具有一致的关联。例如，小鼠黑色素瘤中的 Atg7 3′ UTR 强制延长可抑制 ATG7 蛋白水平，减缓肿瘤生长，提高宿主存活率;同样，在临床人类黑色素瘤中，长 ATG7 3' UTR 与患者生存期显着延长相关。总体而言，我们的研究提供了一种易于适应的方法，可以在生理系统中对 APA 进行功能剖析，并直接量化复发性 APA 事件对致瘤表型的贡献。