Salinas María Dolores, Rodriguez Pablo, Rubio Gonzalo, Valdor Rut
Biochemistry, Molecular Biology B and Immunology Department, University of Murcia (UMU), 30120 Murcia, Spain.
Unit of Autophagy, Immune Response and Tolerance in Pathologic Processes, Biomedical Research Institute of Murcia (IMIB), 30120 Murcia, Spain.
Int J Mol Sci. 2024 Dec 29;26(1):192. doi: 10.3390/ijms26010192.
Glioblastoma (GB) is one of the most aggressive and treatment-resistant cancers due to its complex tumor microenvironment (TME). We previously showed that GB progression is dependent on the aberrant induction of chaperone-mediated autophagy (CMA) in pericytes (PCs), which promotes TME immunosuppression through the PC secretome. The secretion of extracellular matrix (ECM) proteins with anti-tumor (Lumican) and pro-tumoral (Osteopontin, OPN) properties was shown to be dependent on the regulation of GB-induced CMA in PCs. As biomarkers are rarely studied in TME, in this work, we aimed to validate Lumican and OPN as prognostic markers in the perivascular areas of the peritumoral niche of a cohort of GB patients. Previously, we had validated their expression in GB xenografted mice presenting GB infiltration (OPN) or GB elimination (Lumican) dependent on competent or deficient CMA PCs, respectively. Then, patient sample classification by GB infiltration into the peritumoral brain parenchyma was related to GB-induced CMA in microvasculature PCs, analyzing the expression of the lysosomal receptor, LAMP-2A. Our results revealed a correlation between GB-induced CMA activity in peritumoral PCs and GB patients' outcomes, identifying three degrees of severity. The perivascular expression of both immune activation markers, Iba1 and CD68, was related to CMA-dependent PC immune function and determined as useful for efficient GB prognosis. Lumican expression was identified in perivascular areas of patients with less severe outcome and partially co-localizing with PCs presenting low CMA activity, while OPN was primarily found in perivascular areas of patients with poor outcome and partially co-localizing with PCs presenting high CMA activity. Importantly, we found sex differences in the incidence of middle-aged patients, being significantly higher in men but with worse prognosis in women. Our results confirmed that Lumican and OPN in perivascular areas of the GB peritumoral niche are effective predictive biomarkers for evaluating prognosis and monitoring possible therapeutic immune responses dependent on PCs in tumor progression.
胶质母细胞瘤（GB）是最具侵袭性且对治疗耐药的癌症之一，因其肿瘤微环境（TME）复杂。我们之前表明，GB的进展依赖于周细胞（PCs）中伴侣介导的自噬（CMA）的异常诱导，这通过PCs的分泌组促进TME免疫抑制。具有抗肿瘤（纤连蛋白聚糖）和促肿瘤（骨桥蛋白，OPN）特性的细胞外基质（ECM）蛋白的分泌被证明依赖于GB诱导的PCs中CMA的调节。由于生物标志物在TME中很少被研究，在这项工作中，我们旨在验证纤连蛋白聚糖和OPN作为一组GB患者肿瘤周围微环境血管周围区域的预后标志物。此前，我们已经分别在表现出GB浸润（OPN）或GB清除（纤连蛋白聚糖）的GB异种移植小鼠中验证了它们的表达，这分别取决于有功能或缺陷的CMA PCs。然后，通过GB浸润到肿瘤周围脑实质对患者样本进行分类，与微血管PCs中GB诱导的CMA相关，分析溶酶体受体LAMP - 2A的表达。我们的结果揭示了肿瘤周围PCs中GB诱导的CMA活性与GB患者预后之间的相关性，确定了三个严重程度等级。免疫激活标志物Iba1和CD68的血管周围表达与CMA依赖的PC免疫功能相关，并被确定对有效的GB预后有用。纤连蛋白聚糖表达在预后较轻的患者血管周围区域被发现，并与CMA活性低的PCs部分共定位，而OPN主要在预后较差的患者血管周围区域被发现，并与CMA活性高的PCs部分共定位。重要的是，我们发现中年患者的发病率存在性别差异，男性显著更高，但女性预后更差。我们的结果证实，GB肿瘤周围微环境血管周围区域的纤连蛋白聚糖和OPN是有效的预测生物标志物，可用于评估预后以及监测肿瘤进展中依赖于PCs的可能治疗性免疫反应。
