Expression of IMPACT curtails metabolic plasticity and augments NK cell killing to abrogate metastatic growth.

IF 33.3 1区医学 Q1 ONCOLOGY

Cancer discovery Pub Date : 2025-07-31 DOI:10.1158/2159-8290.cd-24-1055

Surajit Sinha,Abir Kumar Panda,Rodrigo Xavier das Neves,Zeribe C Nwosu,Ke Xu,Elke van Beek,Priyanka P Desai,Sivasish Sindiri,Sruthi Chempati,Kirsten Remmert,Billel Gasmi,Linda Bojmar,Constantinos Zambirinis,Alexander J Rossi,Reed I Ayabe,Michael M Wach,James D McDonald,Samantha M Ruff,Emily A Verbus,Areeba Saif,Alyssa V Eade,Carolina M Larrain,Lindsay R Friedman,Shreya Gupta,Alok Ranjan,Martha E Teke,Tahsin M Khan,Tracey Pu,Amber Leila Sarvestani,Carrie E Ryan,Jacob T Lambdin,Kenneth Luberice,Stephanie N Gregory,Stephanie C Lux,Hanna Hong,Allen J Luna,Imani A Alexander,Sarfraz R Akmal,Shahyan U Rehman,Ashley Rainey,Todd D Prickett,Vishal N Koparde,Samantha Sevilla,Skyler A Kuhn,King Chan,Zhonghe Sun,Nina Bubunenko,Eileen Li,Cathleen Hannah,Geneti Gaga,Thorkell Andresson,Margaret C Cam,Xiaolin Wu,Lisa M Jenkins,Andrew M Blakely,Jeremy L Davis,Giorgio Trinchieri,Pankaj K Singh,James C Yang,Marina Pasca di Magliano,Costas A Lyssiotis,Michael B Yaffe,Ethan M Shevach,Jonathan M Hernandez

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引用次数: 0

Abstract

Given the propensity of aggressive epithelial tumors to form hepatic metastases, we performed an in vivo cDNA screen using the mouse liver and KRASG12D/TP53R273H pancreatic cells to identify the RNA binding protein GCN1 as integral component of hepatic outgrowth. RNAi experiments reveal that GCN1 triggers the ISR to activate serine, folate, and methionine biosynthetic pathways together with amino acid transporters, which act in concert to facilitate acquisition of metabolites and to restore redox homeostasis. Alongside activation of the ISR, we found that GCN1 also functions in the nucleus where it interacts with HNRNPK to suppress the expression of MHC-I molecules, and natural killer (NK) ligands. Intriguingly, we identified IMPACT as an endogenous competitive inhibitor of GCN1 that blocks both ISR-dependent metabolic control and disrupts HNRNPK interaction. In doing so, IMPACT enhances tumor immunogenicity to unleash NK cell killing, in addition to sensitizing metastatic tumor cells to immune checkpoint blockade (ICB).

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IMPACT的表达降低了代谢可塑性，增加了NK细胞的杀伤，从而消除了转移性生长。

考虑到侵袭性上皮肿瘤形成肝转移的倾向，我们使用小鼠肝脏和KRASG12D/TP53R273H胰腺细胞进行了体内cDNA筛选，以确定RNA结合蛋白GCN1是肝脏生长的组成部分。RNAi实验表明，GCN1触发ISR激活丝氨酸、叶酸和蛋氨酸生物合成途径以及氨基酸转运蛋白，这些途径协同作用，促进代谢物的获取并恢复氧化还原稳态。除了激活ISR外，我们发现GCN1还在细胞核中与HNRNPK相互作用以抑制MHC-I分子和自然杀伤（NK）配体的表达。有趣的是，我们发现IMPACT是GCN1的内源性竞争性抑制剂，它阻断isr依赖性代谢控制并破坏HNRNPK相互作用。在这样做时，IMPACT增强肿瘤免疫原性，释放NK细胞杀伤，除了使转移性肿瘤细胞对免疫检查点阻断（ICB）敏感之外。

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

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.