STAT3 sustains tumorigenicity following mutant KRAS ablation.

IF 6.2 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2025-08-26 DOI:10.1038/s44319-025-00563-w

Stephen D'Amico, Varvara Kirillov, Jingxuan Liu, Zhijuan Qiu, Xinyuan Lei, Hong Qin, Brian S Sheridan, Nancy C Reich

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引用次数: 0

Abstract

Oncogenic KRAS mutations underlie some of the deadliest human cancers. Genetic or pharmacological KRAS inactivation produces mixed outcomes and frequent relapse. Mechanisms of tumor resistance to KRAS inhibition remain poorly understood. We present evidence that STAT3 supports tumor growth following KRAS depletion. Using a conceptual framework of pancreatic ductal adenocarcinoma, we show that cancer cells that survive CRISPR-mediated ablation of mutant KRAS are dependent on STAT3 function to maintain tumorigenicity. Mechanistically, the combined loss of mutant KRAS and STAT3 disrupts a core transcriptional program of cancer cells critical to oncogenic competence. This in turn impairs tumor growth in mice and enhances immune rejection, leading to tumor clearance. We propose that the STAT3 transcriptional program operating in cancer cells enforces their malignant identity, rather than providing classical features of transformation, and shapes cancer persistence following KRAS inactivation. Our findings establish STAT3 as a critical enforcer of oncogenic identity in KRAS-ablated tumors, revealing a key vulnerability.

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突变KRAS消融后STAT3维持致瘤性。

致癌的KRAS突变是一些最致命的人类癌症的基础。遗传或药理学KRAS失活产生复杂的结果和频繁的复发。肿瘤对KRAS抑制的耐药机制尚不清楚。我们提出证据表明STAT3支持KRAS耗竭后的肿瘤生长。利用胰腺导管腺癌的概念框架，我们发现在crispr介导的KRAS突变消融中存活的癌细胞依赖于STAT3功能来维持致瘤性。从机制上讲，KRAS和STAT3突变体的联合缺失破坏了癌细胞的核心转录程序，这对致癌能力至关重要。这反过来又会损害小鼠的肿瘤生长，增强免疫排斥，导致肿瘤清除。我们提出在癌细胞中运作的STAT3转录程序强化了它们的恶性身份，而不是提供经典的转化特征，并在KRAS失活后形成了癌症的持久性。我们的研究结果表明，STAT3在kras消融的肿瘤中是一个关键的致癌特性的执行者，揭示了一个关键的易感性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

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