OLIG2 Is a Determinant for the Relapse of MYC-Amplified Medulloblastoma.
OLIG2 Is a Determinant for the Relapse of MYC-Amplified Medulloblastoma.
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Olig2是MYC扩增的髓母细胞瘤复发的决定因素。
DOI：
10.1158/1078-0432.ccr-22-0527
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发表时间：
2022-10-03
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MYC扩增的髓母细胞瘤（MB）患者预后差，经常复发，因此需要新的治疗方法来预防复发。我们评估了一组小鼠Myc驱动的MB肿瘤、患者MB样本和患者来源的异种移植（PDX）肿瘤中的OLIG 2表达，并分析了PDX系中OLIG 2-高和OLIG 2-低肿瘤的辐射敏感性。我们评估了通过0 LIG 2-CRISPR或小分子抑制剂CT-179抑制0 LIG 2与放射疗法组合对PDX模型中肿瘤进展的影响。我们发现MYC相关MB可以根据OLIG 2蛋白表达分为OLIG 2-高和OLIG 2-低肿瘤。在MYC扩增的MB PDX模型中，OLIG 2-低肿瘤对放射敏感，很少复发，而OLIG 2-高肿瘤对放射具有抗性，并持续复发。在OLIG 2-高肿瘤中，照射消除了大部分肿瘤细胞;然而，当照射后立即检查时，小脑肿瘤床中仍有少量肿瘤细胞，包括OLIG 2-肿瘤细胞和罕见的OLIG 2+肿瘤细胞。所有携带残留耐药肿瘤细胞的动物均出现复发。复发的肿瘤反映了具有富集的0 LIG 2表达的原发性肿瘤的细胞组成。进一步的研究表明，OLIG 2对于复发是必不可少的，因为用CRISPR介导的缺失或用小分子抑制剂CT-179破坏OLIG 2可以防止残留的放射抗性肿瘤细胞的复发。我们的研究表明，OLIG 2是MYC扩增MB的高风险子集中的生物标志物和有效的治疗靶点，OLIG 2抑制剂与放射治疗相结合代表了治疗这种毁灭性疾病的新的有效方法。
Patients with MYC-amplified medulloblastoma (MB) have poor prognosis and frequently develop recurrence, thus new therapeutic approaches to prevent recurrence are needed. We evaluated OLIG2 expression in a panel of mouse Myc-driven MB tumors, patient MB samples, and patient-derived xenograft (PDX) tumors and analyzed radiation sensitivity in OLIG2−high and OLIG2−low tumors in PDX lines. We assessed the effect of inhibition of OLIG2 by OLIG2-CRISPR or the small molecule inhibitor CT-179 combined with radiotherapy on tumor progression in PDX models. We found that MYC-associated MB can be stratified into OLIG2−high and OLIG2−low tumors based on OLIG2 protein expression. In MYC-amplified MB PDX models, OLIG2−low tumors were sensitive to radiation and rarely relapsed, whereas OLIG2−high tumors were resistant to radiation and consistently developed recurrence. In OLIG2−high tumors, irradiation eliminated the bulk of tumor cells; however, a small number of tumor cells comprising OLIG2− tumor cells and rare OLIG2+ tumor cells remained in the cerebellar tumor bed when examined immediately post-irradiation. All animals harboring residual resistant tumor cells developed relapse. The relapsed tumors mirrored the cellular composition of the primary tumors with enriched OLIG2 expression. Further studies demonstrated that OLIG2 was essential for recurrence, as OLIG2 disruption with CRISPR-mediated deletion or with the small-molecule inhibitor CT-179 prevented recurrence from the residual radioresistant tumor cells. Our studies reveal that OLIG2 is a biomarker and an effective therapeutic target in a high-risk subset of MYC-amplified MB, and OLIG2 inhibitor combined with radiotherapy represents a novel effective approach for treating this devastating disease.