CEACAM6 orchestrates gallbladder cancer aggressiveness through molecular interplay with Integrin and PRKCD [GB-d1]

Gallbladder cancer (GBC) comprises the most common biliary tract cancer (BTC). However, GBC is a rare disease often manifesting as aggressive malignancy due to its late diagnosis and resistance to chemotherapy. The identification of molecular drivers of GBC and identification of targeted therapies is still urgently needed. This study combined proteomic analysis of GBC patient samples, functional and molecular characterization of potential oncogenes, and identification of potential therapy strategy for GBC. We identified Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) as one of the strongest and most significant upregulated proteins in GBC samples. Functional analysis and in vivo mouse models revealed that CEACAM6 supported the initial steps of cancer metastasis by decreasing cell adhesion while promoting migration and invasion of GBC cells. 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 in supporting GBC cell migration through regulation of ERK and AKT downstream target genes MMP13, MMP14, and OCLN. Conversely, CEACAM6 knockdown abolished GBC aggressiveness, and treatment using AKT inhibitor Capivasertib and ERK inhibitor Ulixertinib counter-acted the CEACAM6-induced migration.These findings demonstrate that CEACAM6 is crucial for gallbladder oncogenesis through ERK and AKT signaling, providing insights into the design of therapeutic strategies for GBC.