Fan Linyuan, Liu Yi, Zhou Haichao, Feng Yang, Jiang Guangyi, Hou Guixue, Cao Zhihan, Zheng Zhiguo, Sun Lu, Chen Hao, Zhang Yuefei, Chen Weiran, Xi Yun, Cheng Benliang, Yang Qinghai, Ren Yan, Zhu Jianqing, Liu Siqi
College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
BGI-Shenzhen, Shenzhen, China.
Clin Transl Med. 2025 Jul;15(7):e70422. doi: 10.1002/ctm2.70422.
High-grade serous ovarian carcinoma (HGSC) is a lethal malignancy characterized by high incidence, mortality, and chemoresistance. However, its molecular drivers are unknown. In this study, spatially resolved proteomics was applied to 1144 formalin-fixed paraffin-embedded tissue spots obtained by laser capture microdissection from 10 patients with HGSC and divergent carboplatin-paclitaxel (CP) responses. Specific sampling revealed stroma-driven tumour heterogeneity, identifying 642 tumour-specific and 180 stroma-specific proteins, with 505 CP-responsive therapeutic targets. Most of these protein signatures represented previously unreported associations with chemoresistance in HGSCs. Two clinically significant spatial proteomic maps were generated by introducing tumour (TS) and chemical (CS) scores. TS analysis revealed conserved tissue architecture across CP response groups, whereas CS mapping revealed pretreatment metabolic reprogramming (rather than proliferation) as the defining feature of chemo-resistant tumours, challenging current resistance paradigms. Immunohistochemical validation of HGSC tissue microarrays confirmed the spatial proteomic localization of TFRC and PDLIM3, which are linked to tumour progression, while establishing their novel role as chemotherapy resistance biomarkers through this study, with broader predictive potential observed across additional targets in the discovery cohort. This study developed a spatially resolved proteomic framework to enhance the diagnostic and therapeutic strategies for HGSC. KEY POINTS: HGSC intra-tumour heterogeneity is predominantly driven by stroma, as revealed by spatial proteomic compartmentalization (tumour/stroma). Spatial proteomics expands the therapeutic target database, enabling prediction of platinum-based chemotherapy response. Chemo-resistant patients exhibit pre-treatment metabolic activation rather than proliferative signatures. TFRC (iron transport) and PDLIM3 (cytoskeletal remodelling) are spatially validated as chemo-response biomarkers.
高级别浆液性卵巢癌（HGSC）是一种致命的恶性肿瘤，具有高发病率、高死亡率和化疗耐药性的特点。然而，其分子驱动因素尚不清楚。在本研究中，空间分辨蛋白质组学应用于通过激光捕获显微切割从10例HGSC患者及不同卡铂-紫杉醇（CP）反应中获得的1144个福尔马林固定石蜡包埋组织样本点。特异性采样揭示了基质驱动的肿瘤异质性，鉴定出642种肿瘤特异性蛋白和180种基质特异性蛋白，其中有505个CP反应性治疗靶点。这些蛋白质特征中的大多数代表了此前未报道的与HGSCs化疗耐药性的关联。通过引入肿瘤（TS）和化学（CS）评分生成了两个具有临床意义的空间蛋白质组图谱。TS分析揭示了CP反应组间保守的组织结构，而CS图谱显示预处理代谢重编程（而非增殖）是化疗耐药肿瘤的决定性特征，这对当前的耐药模式提出了挑战。HGSC组织微阵列的免疫组化验证证实了TFRC和PDLIM3的空间蛋白质组定位，它们与肿瘤进展相关，同时通过本研究确立了它们作为化疗耐药生物标志物的新作用，在发现队列中的其他靶点上观察到了更广泛的预测潜力。本研究开发了一种空间分辨蛋白质组学框架，以加强HGSC的诊断和治疗策略。要点：空间蛋白质组学分区（肿瘤/基质）显示，HGSC肿瘤内异质性主要由基质驱动。空间蛋白质组学扩展了治疗靶点数据库，能够预测铂类化疗反应。化疗耐药患者表现出预处理代谢激活而非增殖特征。TFRC（铁转运）和PDLIM3（细胞骨架重塑）在空间上被验证为化疗反应生物标志物。
