Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.
Department of Neurological Surgery, Helen Diller Research Center, University of California San Francisco, San Francisco, CA, USA.
Nat Commun. 2021 Jan 4;12(1):92. doi: 10.1038/s41467-020-20312-y.
Telomere maintenance is a universal hallmark of cancer. Most tumors including low-grade oligodendrogliomas use telomerase reverse transcriptase (TERT) expression for telomere maintenance while astrocytomas use the alternative lengthening of telomeres (ALT) pathway. Although TERT and ALT are hallmarks of tumor proliferation and attractive therapeutic targets, translational methods of imaging TERT and ALT are lacking. Here we show that TERT and ALT are associated with unique H-magnetic resonance spectroscopy (MRS)-detectable metabolic signatures in genetically-engineered and patient-derived glioma models and patient biopsies. Importantly, we have leveraged this information to mechanistically validate hyperpolarized [1-C]-alanine flux to pyruvate as an imaging biomarker of ALT status and hyperpolarized [1-C]-alanine flux to lactate as an imaging biomarker of TERT status in low-grade gliomas. Collectively, we have identified metabolic biomarkers of TERT and ALT status that provide a way of integrating critical oncogenic information into non-invasive imaging modalities that can improve tumor diagnosis and treatment response monitoring.
端粒维持是癌症的普遍标志。大多数肿瘤，包括低级别少突胶质细胞瘤，使用端粒酶逆转录酶（TERT）表达来维持端粒，而星形细胞瘤则使用端粒的替代性延长（ALT）途径。虽然 TERT 和 ALT 是肿瘤增殖的标志，也是有吸引力的治疗靶点，但缺乏用于成像 TERT 和 ALT 的转化方法。在这里，我们展示了 TERT 和 ALT 与基因工程和患者来源的神经胶质瘤模型以及患者活检中的独特 H-磁共振波谱（MRS）可检测代谢特征相关。重要的是，我们利用这些信息从机制上验证了将[1-C]-丙氨酸到丙酮酸的极化作为 ALT 状态的成像生物标志物，以及将[1-C]-丙氨酸到乳酸的极化作为低级别神经胶质瘤中 TERT 状态的成像生物标志物。总的来说，我们已经确定了 TERT 和 ALT 状态的代谢生物标志物，为将关键致癌信息整合到可以改善肿瘤诊断和治疗反应监测的非侵入性成像方式提供了一种方法。
