IRS2 as a driver of brain metastasis in colorectal cancer: A potential target for novel therapeutic strategies.

IF 13.4 1区医学 Q1 CLINICAL NEUROLOGY

Neuro-oncology Pub Date : 2025-09-08 DOI:10.1093/neuonc/noaf028

Inbal Greenberg, Fayhaa Khair-Dabour, Keren Merenbakh-Lamin, Ethan S Sokol, Anat Klein Goldberg, Dor Simkin, Avishay Spitzer, Moshe Benhamou, Shai Bar-Shira, Michal Raz, Rachel Grossman, Eilam Yeini, Paula Ofek, Tomer Meirson, Ronit Satchi-Fainaro, Hadas Reuveni, Ido Wolf, Tami Rubinek

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引用次数: 0

Abstract

Background: Colorectal cancer (CRC) ranks as the fourth most common cause of brain metastasis (BM), with its incidence on the rise. However, the molecular mechanisms driving the formation of these lesions from CRC remain unclear.

Methods: We analyzed the Foundation Medicine genomic database, which includes over 35,000 CRC samples from both local and metastatic sites. The role of insulin receptor substrate 2 (IRS2) in CRC brain tropism was investigated using various in vitro (co-culture systems and 3D sphere formation assays), in vivo (intracranial and subcutaneous mouse models), and ex vivo (CRC Patient-Derived Explants) models. The molecular and metabolic effects of IRS2 were examined through RNA sequencing and Seahorse analysis. The therapeutic potential of a combined treatment with NT219, an IRS2 inhibitor, and 5-fluorouracil (5-FU) was assessed using our CRC BM mouse model.

Results: Our research reveals a distinctive genomic profile of CRC BM and highlights the role of IRS2 in promoting CRC BM. IRS2 mediates its effect by modulating the β-catenin and oxidative phosphorylation (OXPHOS) pathways. We developed a mouse model of BM from CRC and demonstrated that treatment with the IRS2 inhibitor NT219, in combination with 5-FU, significantly suppresses BM development and prolongs survival.

Conclusions: Our work underscores the unique role of IRS2 in facilitating CRC brain adaptation and suggests a novel therapeutic strategy for CRC patients with BM.

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IRS2作为结直肠癌脑转移的驱动因素：新治疗策略的潜在靶点

背景：结直肠癌（CRC）是脑转移（BM）的第四大常见原因，其发病率呈上升趋势。然而，驱动结直肠癌形成这些病变的分子机制尚不清楚。方法：我们分析了FoundationOne基因组数据库，其中包括来自局部和转移部位的35000多个CRC样本。胰岛素受体底物2 （IRS2）在CRC脑向性中的作用通过各种体外（共培养系统和3D球体形成试验），体内（颅内和皮下小鼠模型）和体外（CRC患者源性外植体（PDE））模型进行了研究。通过RNA测序和海马分析检测IRS2的分子和代谢作用。使用我们的CRC BM小鼠模型评估了NT219（一种IRS2抑制剂）和5-氟尿嘧啶（5-FU）联合治疗的治疗潜力。结果：我们的研究揭示了CRC BM的独特基因组图谱，并强调了IRS2在促进CRC BM中的作用。IRS2通过调节β-catenin和氧化磷酸化（OXPHOS）途径介导其作用。我们建立了来自CRC的BM小鼠模型，并证明IRS2抑制剂NT219与5-FU联合治疗可显著抑制BM的发展并延长生存期。结论：我们的工作强调了IRS2在促进结直肠癌脑适应中的独特作用，并为结直肠癌合并BM患者提供了一种新的治疗策略。

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

Neuro-oncology 医学-临床神经学

CiteScore

27.20

自引率

6.30%

发文量

1434

审稿时长

3-8 weeks

期刊介绍： Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field. The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.