Dhotare Priyanka S, Bochi-Layec Audrey C, Fleming Timothy P, Gillanders William E, Bremner Ross M, Sonawane Kailas D, Sankpal Narendra V
Shivaji University, Kolhapur, 416004, India.
School of Medicine, Washington University, St. Louis, 63110, USA.
BMC Cancer. 2025 Jul 1;25(1):1066. doi: 10.1186/s12885-025-14455-8.
EpCAM (epithelial cell adhesion molecule) is a key regulator of epithelial cell-cell adhesion, signal transduction, tissue regeneration, and serves as a stem cell marker. It is frequently overexpressed in epithelial cancers and is linked to tumor progression, survival, and metastasis. However, the functional impact of EpCAM mutations in cancer remains poorly understood.
To investigate the role of EpCAM mutations, we performed a comprehensive analysis of cancer cohorts from multiple genomic datasets, identifying novel somatic EpCAM mutations across diverse epithelial cancers. Using bioinformatics tools (SIFT, PolyPhen-2, Mutation Assessor) and molecular modeling, we assessed the potential impact of these mutations. Further, homology modeling and all-atom molecular dynamics (MD) simulations were conducted to evaluate structural changes. From an analysis of 300 studies comprising 300,300 cancer samples, we identified 160 recurrent somatic mutations across epithelial cancers. Of these, seven mutations most frequently associated with lung cancer were further validated through molecular dynamics simulations, evaluation of ERK signaling activity, and assessment of sensitivity to the MEK inhibitor Trametinib.
Our findings revealed that cancer-associated mutations, particularly in the TY-1 and RCD regions, induce structural instability in EpCAM, leading to altered functional properties. Patient cohort analyses indicated that EpCAM mutations correlate with reduced survival rates in colon and hepatocellular carcinoma and contribute to early tumor progression in lung cancer. Moreover, introducing these mutations into lung cancer cells enhanced their sensitivity to MEK inhibitors, suggesting a potential therapeutic vulnerability.
This study provides novel insights into the structural and functional consequences of EpCAM mutations in cancer, demonstrating their association with reduced survival, tumor progression, and drug sensitivity. These findings highlight EpCAM as a promising therapeutic target in epithelial cancers.
上皮细胞粘附分子（EpCAM）是上皮细胞间粘附、信号转导、组织再生的关键调节因子，也是一种干细胞标志物。它在上皮性癌中经常过度表达，并与肿瘤进展、生存及转移相关。然而，EpCAM突变在癌症中的功能影响仍知之甚少。
为研究EpCAM突变的作用，我们对多个基因组数据集的癌症队列进行了全面分析，在多种上皮性癌中鉴定出新的体细胞EpCAM突变。使用生物信息学工具（SIFT、PolyPhen-2、Mutation Assessor）和分子建模，我们评估了这些突变的潜在影响。此外，进行了同源建模和全原子分子动力学（MD）模拟以评估结构变化。通过对包含300,300个癌症样本的300项研究的分析，我们在各种上皮性癌中鉴定出160个复发性体细胞突变。其中，通过分子动力学模拟、ERK信号活性评估以及对MEK抑制剂曲美替尼敏感性评估，进一步验证了与肺癌最常相关的七个突变。
我们的研究结果表明，癌症相关突变，尤其是在TY-1和RCD区域的突变，会导致EpCAM结构不稳定，从而改变其功能特性。患者队列分析表明，EpCAM突变与结肠癌和肝细胞癌的生存率降低相关，并促进肺癌的早期肿瘤进展。此外，将这些突变引入肺癌细胞会增强它们对MEK抑制剂的敏感性，提示存在潜在的治疗易损性。
本研究为EpCAM突变在癌症中的结构和功能后果提供了新见解，证明它们与生存率降低、肿瘤进展和药物敏感性相关。这些发现突出了EpCAM作为上皮性癌中有前景的治疗靶点。
