Hsiao Ting-Feng, Wang Chih-Liang, Wu Yi-Cheng, Kuo Chia-Yu, Lin Ke-Wei, Chuang Wen-Yu, Yeh Chi-Ju, Wu Chia-Chun, Liu Ko-Jiunn, Chang Gee-Chen, Chien Kun-Yi, Yu Jau-Song, Yu Chia-Jung
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan.
J Proteome Res. 2025 Sep 5;24(9):4674-4688. doi: 10.1021/acs.jproteome.5c00385. Epub 2025 Aug 2.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have transformed lung adenocarcinoma (LUAD) treatment in EGFR-mutant (MT) patients, but strategies targeting wild-type (WT) EGFR tumors remain necessary. This study analyzed a diverse LUAD patient cohort with EGFR mutation statuses and wild-type profiles for ALK and KRAS to identify stage-specific biomarkers. Using quantitative proteomics and multiomics, we discovered 21 dysregulated proteins in early-stage EGFR-WT LUAD, identifying myeloid-derived growth factor (MYDGF) as a key candidate biomarker. Elevated MYDGF levels in tissue ( = 117) and serum ( = 196) correlated significantly with cancer stage in EGFR-WT patients but not EGFR-MT cases. Notably, a higher tumor-to-normal MYDGF ratio predicted a favorable prognosis in early-stage EGFR-WT LUAD. Functional studies demonstrated that MYDGF exerts distinct roles in cell viability and migration depending on its cellular localization and the invasive potential of cancer cells. Specifically, secreted MYDGF promoted a protumorigenic phenotype, whereas excess intracellular MYDGF appeared to suppress the oncogenic capacity of aggressive cancer cells. MYDGF knockdown and subsequent proteomic analysis provided further insights into these context-dependent functions. These findings highlight EGFR status- and stage-specific proteomic profiles in LUAD, emphasizing the importance of context-dependent biomarker assessment for personalized treatment strategies.
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂已改变了表皮生长因子受体突变（MT）的肺癌（LUAD）患者的治疗方式，但针对野生型（WT）EGFR肿瘤的治疗策略仍然很有必要。本研究分析了一组具有EGFR突变状态以及ALK和KRAS野生型特征的不同LUAD患者队列，以确定阶段特异性生物标志物。通过定量蛋白质组学和多组学技术，我们在早期EGFR-WT LUAD中发现了21种失调蛋白，确定髓系衍生生长因子（MYDGF）为关键候选生物标志物。在组织（n = 117）和血清（n = 196）中，MYDGF水平升高与EGFR-WT患者的癌症分期显著相关，但与EGFR-MT患者无关。值得注意的是，肿瘤与正常组织的MYDGF比值较高预示着早期EGFR-WT LUAD患者预后良好。功能研究表明，MYDGF根据其细胞定位和癌细胞的侵袭潜力在细胞活力和迁移中发挥不同作用。具体而言，分泌型MYDGF促进促肿瘤表型，而过量的细胞内MYDGF似乎抑制侵袭性癌细胞的致癌能力。MYDGF敲低及随后的蛋白质组学分析为这些依赖于背景的功能提供了进一步的见解。这些发现突出了LUAD中EGFR状态和阶段特异性蛋白质组学特征，强调了依赖于背景的生物标志物评估对个性化治疗策略的重要性。
