Mena (ENAH) Promotes KRAS-Driven Tumor Growth and Metastatic Progression in Pancreatic Ductal Adenocarcinoma

ABSTRACT Metastatic pancreatic ductal adenocarcinoma (PDAC) remains incurable and is projected to become the second leading cause of cancer-related death by 2030. Despite therapeutic advances, median survival remains under one year. Activating KRAS mutations drive the majority of PDAC and underlie their highly aggressive behavior. Although emerging KRAS inhibitors show promise, resistance limits their clinical efficacy, underscoring the need to identify additional regulators of mutant KRAS signaling. We investigated the role of the actin-regulatory protein Mena (ENAH) in KRAS G12D -driven PDAC using novel in vitro and orthotopic in vivo models with Mena overexpression and knockdown. Mena overexpression markedly increased primary tumor growth and spontaneous liver metastasis, whereas Mena knockdown delayed tumor onset and reduced metastatic burden. Mechanistically, Mena depletion significantly decreased AKT and ERK activity downstream of KRAS in a SHIP2-mediated manner, indicating that Mena enhances oncogenic signaling required for PDAC progression. These findings reveal Mena as a critical modulator of KRAS G12D -driven pancreatic tumor growth and metastasis. By promoting key survival and proliferation pathways, Mena contributes to the aggressive phenotype characteristic of KRAS-mutant PDAC and represents a promising therapeutic target for patients with both locoregional and metastatic disease.