软组织肉瘤细胞外基质网络的临床意义和分子特征。
Clinical implications and molecular features of extracellular matrix networks in soft tissue sarcomas.
发表日期：2024 May 29
作者：
Valeriya Pankova, Lukas Krasny, William Kerrison, Yuen Bun Tam, Madhumeeta Chadha, Jessica Burns, Christopher P Wilding, Liang Chen, Avirup Chowdhury, Emma Perkins, Alexander T J Lee, Louise Howell, Nafia Guljar, Karen Sisley, Cyril Fisher, Priya Chudasama, Khin Thway, Robin L Jones, Paul H Huang
来源：
Protein & Cell
摘要：
软组织肉瘤 (STS) 中细胞外基质 (ECM) 变化的情况仍然知之甚少。我们的目的是研究 STS 中存在的肿瘤 ECM 和粘附信号网络及其临床意义。分析了 11 种组织学亚型的 321 名患者的蛋白质组学和临床数据，以定义 ECM 和整合素粘附网络。对平滑肌肉瘤 (LMS)、去分化脂肪肉瘤 (DDLPS) 和未分化多形性肉瘤 (UPS) 进行亚组分析。该分析定义了亚型特异性 ECM 谱，包括 LMS 中基底膜蛋白的富集和 UPS 中 ECM 蛋白酶的富集。在整个队列中，我们确定了三个不同的共同调节的 ECM 网络，它们与肿瘤恶性程度和组织学亚型相关。 LMS 细胞系和患者蛋白质组数据的比较分析确定 LCP1 细胞骨架蛋白是 LMS 的预后因素。 DDLPS 中 ECM 网络事件的表征揭示了具有不同致癌信号通路和生存结果的三种亚型。对预后最差的 DDLPS 亚型的评估提名 ECM 重塑蛋白作为候选抗基质治疗靶点。最后，我们定义了一个蛋白聚糖特征，它是 DDLPS 和 UPS 总体生存的独立预后因素。STS 包含异质 ECM 信号网络和基质特异性特征，可用于风险分层和治疗选择，未来可以指导这些罕见疾病的精准医疗。癌症。
The landscape of extracellular matrix (ECM) alterations in soft tissue sarcomas (STS) remains poorly characterised. We aimed to investigate the tumour ECM and adhesion signalling networks present in STS and their clinical implications.Proteomic and clinical data from 321 patients across 11 histological subtypes were analysed to define ECM and integrin adhesion networks. Subgroup analysis was performed in leiomyosarcomas (LMS), dedifferentiated liposarcomas (DDLPS) and undifferentiated pleiomorphic sarcomas (UPS).This analysis defined subtype-specific ECM profiles including enrichment of basement membrane proteins in LMS and ECM proteases in UPS. Across the cohort, we identified three distinct co-regulated ECM networks which are associated with tumour malignancy grade and histological subtype. Comparative analysis of LMS cell line and patient proteomic data identified the LCP1 cytoskeletal protein as a prognostic factor in LMS. Characterisation of ECM network events in DDLPS revealed three subtypes with distinct oncogenic signalling pathways and survival outcomes. Evaluation of the DDLPS subtype with the poorest prognosis nominates ECM remodelling proteins as candidate anti-stromal therapeutic targets. Finally, we define a proteoglycan signature which is an independent prognostic factor for overall survival in DDLPS and UPS.STS comprise heterogeneous ECM signalling networks and matrix-specific features have utility for risk stratification and therapy selection which could in future guide precision medicine in these rare cancers.