PO.CH02.01 · 化学
细胞外激酶组网络揭示分泌型激酶FAM20C是口腔鳞状细胞癌复发的关键驱动因素
Extracellular kinome network reveals secretory kinase FAM20C as a key driver of recurrence in oral squamous cell carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
口腔鳞状细胞癌（OSCC）是一种高度侵袭性的恶性肿瘤，复发率达40-60%，即使在明确治疗后也常表现出局部区域复发和淋巴结转移。肿瘤进展和复发不仅由癌细胞的内在特征驱动，还由与周围肿瘤微环境（TME）的复杂相互作用驱动。为探索复发相关的调控通路，我们对34名OSCC患者的血浆进行了基于LC-MS/MS的磷酸化蛋白质组学分析，识别出113种携带261个磷酸化位点的磷酸化蛋白，这些蛋白富集于脂质结合、补体激活、细胞外基质（ECM）组织和钙结合功能。主成分和相关性分析将复发患者与无复发患者区分开来，共识聚类揭示了三种磷酸化-分泌亚型。值得注意的是，预后不良的亚型表现出S-x-E基序内磷酸化丝氨酸的富集。这一模式提示分泌型丝氨酸激酶FAM20C的激活，其磷酸化定位于ER/Golgi的分泌蛋白和膜胞外结构域底物。公共数据集证实高FAM20C表达与复发风险增加以及总生存和无进展生存降低相关。为验证这些发现，我们检查了源自本队列的患者来源类器官（PDO）和癌症相关成纤维细胞（CAF）。在源自复发肿瘤的PDO中，FAM20C的表达和分泌均显著升高，来自复发患者的CAF也表现出FAM20C分泌增加。在功能上，FAM20C过表达增强了侵袭、ECM重塑和EMT激活，而FAM20C敲低抑制了间充质标志物、减少了TGF-beta-SMAD2/3信号，并抑制了包括SOX2、OCT4、CD44、NANOG、MYC和CD133在内的干性相关基因。总之，这些发现将FAM20C识别为复发相关细胞外信号的关键调控因子，并凸显了其作为OSCC复发预后生物标志物的潜力。
查看英文原文 English abstract
Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy with a recurrence rate of 40-60%, frequently exhibiting locoregional relapse and lymph node metastasis even after definitive treatment. Tumor progression and recurrence are driven not only by intrinsic characteristics of cancer cells but also by complex interactions with the surrounding tumor microenvironment (TME). To explore recurrence-associated regulatory pathways, we performed LC-MS/MS-based phosphoproteomic profiling of plasma from 34 OSCC patients and identified 113 phosphoproteins harboring 261 phosphosites enriched in lipid binding, complement activation, extracellular matrix (ECM) organization, and calcium-binding functions. Principal component and correlation analyses distinguished patients with recurrence from those without, and consensus clustering revealed three phospho-secretory subtypes. Notably, the subtype with the poor prognosis exhibited a enrichment of phospho-serine within the S-x-E motif. This pattern suggested activation of the secreted serine kinase FAM20C, which phosphorylates ER/Golgi-localized secretory proteins and membrane ectodomain substrates. Public datasets confirmed that high FAM20C expression correlates with increased recurrence risk and reduced overall and progression-free survival. To validate these findings, we examined patient-derived organoids (PDOs) and cancer-associated fibroblasts (CAFs) established from our cohort. Both FAM20C expression and secretion were markedly elevated in PDOs derived from recurrent tumors, and CAFs from recurrent patients also exhibited increased FAM20C secretion. Functionally, FAM20C overexpression enhanced invasion, ECM remodeling, and EMT activation, while FAM20C knockdown suppressed mesenchymal markers, reduced TGF-beta-SMAD2/3 signaling, and suppressed stemness-associated genes including SOX2, OCT4, CD44, NANOG, MYC, and CD133. Together, these findings identify FAM20C as a key regulator of recurrence-associated extracellular signaling and highlight its potential as a prognostic biomarker for recurrence in OSCC.
利益披露 Disclosure
M. Lee, None..
Y. Lee, None..
S. Kang, None..
J. Lee, None..
H. Shon, None..
S. Choi, None..
G. Kang, None..
K. Kim, None..
J. Lee, None..
I. Kwon, None..
S. Choi, None..
Y. Kim, None.