Greenberg Inbal, Khair-Dabour Fayhaa, Merenbakh-Lamin Keren, Sokol Ethan S, Goldberg Anat Klein, Simkin Dor, Spitzer Avishay, Benhamou Moshe, Bar-Shira Shai, Raz Michal, Grossman Rachel, Yeini Eilam, Ofek Paula, Meirson Tomer, Satchi-Fainaro Ronit, Reuveni Hadas, Wolf Ido, Rubinek Tami
Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Neuro Oncol. 2025 Sep 8;27(7):1729-1745. doi: 10.1093/neuonc/noaf028.
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.
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.
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.
Our work underscores the unique role of IRS2 in facilitating CRC brain adaptation and suggests a novel therapeutic strategy for CRC patients with BM.
结直肠癌（CRC）是脑转移（BM）的第四大常见病因，其发病率呈上升趋势。然而，CRC形成这些脑转移病灶的分子机制仍不清楚。
我们分析了Foundation Medicine基因组数据库，该数据库包含来自局部和转移部位的超过35000份CRC样本。使用各种体外（共培养系统和三维球体形成试验）、体内（颅内和皮下小鼠模型）和离体（CRC患者来源的外植体）模型研究胰岛素受体底物2（IRS2）在CRC脑嗜性中的作用。通过RNA测序和海马分析检测IRS2的分子和代谢效应。使用我们的CRC BM小鼠模型评估IRS2抑制剂NT219与5-氟尿嘧啶（5-FU）联合治疗的治疗潜力。
我们的研究揭示了CRC BM独特的基因组特征，并突出了IRS2在促进CRC BM中的作用。IRS2通过调节β-连环蛋白和氧化磷酸化（OXPHOS）途径介导其效应。我们建立了一个CRC脑转移小鼠模型，并证明用IRS2抑制剂NT219与5-FU联合治疗可显著抑制脑转移的发展并延长生存期。
我们的工作强调了IRS2在促进CRC脑适应性方面的独特作用，并为患有脑转移的CRC患者提出了一种新的治疗策略。
