Institute of Pathology, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany.
Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), Jena, Germany.
Cell Death Dis. 2024 Oct 28;15(10):780. doi: 10.1038/s41419-024-07171-x.
Gallbladder cancer (GBC) presents as an aggressive malignancy with poor patient outcome. Like other epithelial cancers, the mechanisms of GBC cancer progression remain vague and efforts in finding targeted therapies fall below expectations. This study combined proteomic analysis of formalin-fixed paraffin-embedded (FFPE) GBC samples, functional and molecular characterization of potential oncogenes and identification of potential therapeutic strategies for GBC. We identified Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) as one of the significantly most upregulated proteins in GBC. CEACAM6 overexpression has been observed in other cancer entities but the molecular function remains unclear. Our functional analyses in vitro and in vivo mouse models revealed that CEACAM6 supported the initial steps of cancer progression and metastasis by decreasing cell adhesion and promoting migration and invasion of GBC cells. Conversely, CEACAM6 knockdown abolished GBC aggressiveness by increasing cell adhesion while reducing cell migration, cell proliferation, and colony formation. BirA-BioID followed by mass-spectrometry revealed Integrin Beta-1 (ITGB1) and Protein Kinase C Delta (PRKCD) as direct molecular and functional partners of CEACAM6 supporting GBC cell migration. ERK and AKT signaling and their downstream target genes were regulated by CEACAM6 and thus the treatment with AKT inhibitor capivasertib or ERK inhibitor ulixertinib mitigated the CEACAM6-induced migration. These findings demonstrate that CEACAM6 is crucially involved in gallbladder cancer progression by promoting migration and inhibiting cell adhesion through ERK and AKT signaling providing specific options for treatment of CEACAM6-positive cancers.
胆囊癌（GBC）表现为一种侵袭性恶性肿瘤，患者预后不良。与其他上皮癌一样，GBC 癌症进展的机制仍不清楚，寻找靶向治疗的努力也低于预期。本研究结合了福尔马林固定石蜡包埋（FFPE）GBC 样本的蛋白质组学分析、潜在癌基因的功能和分子特征以及 GBC 潜在治疗策略的鉴定。我们发现癌胚抗原相关细胞粘附分子 6（CEACAM6）是 GBC 中上调最显著的蛋白之一。CEACAM6 的过表达已在其他癌症实体中观察到，但分子功能仍不清楚。我们在体外和体内小鼠模型中的功能分析表明，CEACAM6 通过降低细胞粘附并促进 GBC 细胞的迁移和侵袭，支持癌症进展和转移的初始步骤。相反，CEACAM6 敲低通过增加细胞粘附而减少细胞迁移、细胞增殖和集落形成来消除 GBC 的侵袭性。BirA-BioID 随后进行质谱分析表明，整合素β-1（ITGB1）和蛋白激酶 C 三角洲（PRKCD）是 CEACAM6 的直接分子和功能伙伴，支持 GBC 细胞迁移。ERK 和 AKT 信号及其下游靶基因受 CEACAM6 调节，因此 AKT 抑制剂 capivasertib 或 ERK 抑制剂 ulixertinib 的治疗减轻了 CEACAM6 诱导的迁移。这些发现表明，CEACAM6 通过促进迁移和抑制细胞粘附来参与胆囊癌的进展，通过 ERK 和 AKT 信号通路调节下游靶基因，为治疗 CEACAM6 阳性癌症提供了特定的选择。
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