PO.TB10.18 · 肿瘤生物学
发掘细胞外基质作为新型靶点来源：一个基于基质体的平台以表征肿瘤微环境
Unlocking the extracellular matrix as a source of novel targets: A matrisome-based platform to characterize the tumor microenvironment
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：
细胞外基质（ECM）是一种对肿瘤发生和疾病进展至关重要的生物活性环境。然而，尽管有证据表明存在多个超选择性ECM靶点，利用ECM进行治疗性靶向的努力仍集中于纤连蛋白异构体。
方法：
我们利用一种专注于保留稳定ECM靶点的脱细胞方案，在三种癌症适应症中表征基质体，包括中度至低分化胰腺导管腺癌（PDAC）肿瘤（n = 5；IA-IIB期）、中度分化原发性结直肠癌（CRC）肿瘤（n = 5；I-IIIB期）和CRC肝转移（CRC-LM；n = 5；IV期）。对于每种适应症，我们使用机械和化学方法对肿瘤和背景全组织样本进行脱细胞处理。该方法能够在保留三维ECM结构和组成的同时去除细胞。随后对脱细胞ECM进行组织学分析，并通过TMT DDA质谱（MS）进行蛋白质组学分析。
结果：
对CRC和CRC-LM肿瘤及相邻非肿瘤组织样本的分析鉴定出1,080种共同表达的蛋白，其中79种为核心基质蛋白，67种为基质相关蛋白。肿瘤特异性基质体特征清楚地将肿瘤与非肿瘤相邻组织样本区分开来，两种适应症中分别有83种和96种ECM蛋白在CRC和CRC-LM中差异表达（FDR < 0.05）。对PDAC肿瘤及相邻非肿瘤组织样本的分析检测到854种蛋白，包括103种核心基质体和77种基质体相关蛋白。此外，我们鉴定出一个由109种在肿瘤与背景之间差异调控的ECM蛋白组成的PDAC特征。关键的是，将本研究鉴定的高度富集靶点与批量和单细胞RNA数据进行比较表明，其中许多靶点具有超选择性，因此可作为有价值的ECM稳定候选靶点用于治疗性靶向。
结论：
对脱细胞肿瘤和相邻非肿瘤组织的TMT-MS分析定义了一个新型的、肿瘤特异性的、富集稳定结合蛋白的基质体特征。将该数据集与转录组数据整合，鉴定出可能对治疗性靶向有价值的特定ECM通路和靶点。
查看英文原文 English abstract
Background:
The extracellular matrix (ECM) is a bioactive environment key to tumorigenesis and disease progression. Yet despite evidence that multiple ultra-selective ECM targets exist, efforts to leverage the ECM for therapeutic targeting have remained centered on fibronectin isoforms.
Methods:
We leveraged a decellularization protocol focused on preserving stable ECM targets to characterize the matrisome in three cancer indications, including moderately to poorly differentiated pancreatic ductal adenocarcinoma (PDAC) tumors (n = 5; stage IA-IIB), moderately differentiated primary colorectal cancer (CRC) tumors (n = 5; stages I-IIIB), and CRC liver metastases (CRC-LM; n = 5; stage IV). For each indication, we decellularized tumor and background whole-tissue samples using mechanical and chemical approaches. This method enables the removal of cells while preserving 3D ECM structure and composition. Decellularized ECM was then analyzed histologically and with proteomics via TMT DDA mass spectrometry (MS).
Results:
Analysis of CRC and CRC-LM tumor and adjacent non-tumor tissue samples identified 1,080 commonly expressed proteins, 79 of which were core matrix proteins and 67 matrix-associated. Tumor-specific matrisome signatures clearly differentiated tumor from non-tumor adjacent tissue samples for both indications-83 and 96 ECM proteins were differentially expressed in CRC and CRC-LM, respectively (FDR < 0.05). Analysis of PDAC tumors and adjacent non-tumor tissue samples detected 854 proteins, including 103 core matrisome and 77 matrisome-associated proteins. In addition, we identified a PDAC signature of 109 ECM proteins differentially regulated between tumor and background. Critically, comparison of highly enriched targets identified by this study with both bulk and single-cell RNA data indicated that a number of these targets are ultra-selective and could thus serve as valuable ECM-stable candidates for therapeutic targeting.
Conclusions:
TMT-MS analysis of decellularized tumors and adjacent non-tumor tissues defined a novel, tumor-specific matrisome signature enriched for stably bound proteins. Integration of this dataset with transcriptomic data identified specific ECM pathways and targets that may be valuable for therapeutic targeting.
利益披露 Disclosure
L. Sassi,
Engitix Employment.
S. Mahfouzi,
Engitix Employment.
F. Prestinoni,
Engitix Employment.
T. Vinh,
Engitix Employment.
S. Cooper,
Engitix Employment.