Myeloid-Derived Growth Factor-Regulated Oncogenesis in Lung Adenocarcinoma Is Associated with EGFR Status and Cancer Aggressiveness

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 (n = 117) and serum (n = 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（Epidermal growth factor receptor, EGFR）酪氨酸激酶抑制剂已重塑了EGFR突变型（EGFR-mutant, MT）肺腺癌（lung adenocarcinoma, LUAD）患者的治疗格局，但针对野生型（wild-type, WT）EGFR肿瘤的治疗策略仍有待开发。本研究纳入一组涵盖不同EGFR突变状态、且具备ALK与KRAS野生型特征的多源LUAD患者队列，旨在挖掘分期特异性生物标志物。本研究通过定量蛋白质组学与多组学分析，在早期EGFR野生型LUAD样本中筛选出21个失调蛋白，并鉴定出髓系衍生生长因子（myeloid-derived growth factor, MYDGF）作为关键候选生物标志物。在EGFR野生型患者中，组织（n=117）与血清（n=196）中升高的MYDGF水平与癌症分期显著相关，但在EGFR突变型患者中未观察到该关联。值得注意的是，更高的肿瘤-正常组织MYDGF比值可预测早期EGFR野生型LUAD患者的良好预后。功能实验证实，MYDGF对细胞活力与迁移的调控作用依赖于其细胞定位以及癌细胞的侵袭潜能，发挥截然不同的功能：分泌型MYDGF可促进促肿瘤表型，而过量的细胞内MYDGF则会抑制侵袭性癌细胞的致瘤能力。通过MYDGF敲低及后续蛋白质组学分析，本研究进一步阐明了这些情境依赖的功能机制。本研究结果揭示了LUAD中与EGFR状态及肿瘤分期相关的特异性蛋白质组特征，强调了情境依赖性生物标志物评估在制定个性化治疗策略中的核心价值。