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Abstract

Gallbladder cancer (GBC) comprises the most common biliary tract cancer (BTC), however, it is a rare disease often manifesting as aggressive malignancy due to its late diagnosis and resistance to chemotherapy. There is growing evidence that the molecular profiles of GBC are different from other BTC types and 5-year overall patient survival is less than 20%. Thus, the identification of specific molecular drivers of GBC and the development of targeted therapies are still urgently needed. 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. I identified Carcinoembryonic Antigen-Related Cell Adhesion Molecule 6 (CEACAM6) as one of the strongest and most significantly upregulated proteins in GBC. Functional analysis and in vivo mouse models revealed that CEACAM6 supported the initial steps of cancer progression to metastasis by decreasing cell adhesion and promoting migration and invasion of GBC cells. BirA-BioID followed by mass spectrometry identified Integrin Beta-1 (ITGB1) and Protein Kinase C Delta (PRKCD) as direct molecular and functional partners of CEACAM6 supporting GBC cell migration through regulation of ERK and AKT downstream target genes MMP13, MMP14 and OCLN. Conversely, CEACAM6 knockdown abolished GBC aggressiveness by increasing cell adhesion while reducing cell migration, cell proliferation and colony formation. The AKT inhibitor capivasertib and 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 patients with GBC.