Targeting LTBP2 Derived from Cancer-Associated Fibroblasts Sensitizes Esophageal Squamous Cell Carcinoma to Chemotherapy

Cancer-associated fibroblasts (CAF) are pivotal constituents of the tumor microenvironment that significantly influence cancer aggressiveness through the secretion of various factors. A more detailed characterization of the specific secretions exclusive to CAFs that drive tumor progression could identify potential targets to perturb this intracellular cross-talk. In this study, we identified latent TGFβ-binding protein 2 (LTBP2) as a unique protein secreted exclusively by esophageal squamous cell carcinoma (ESCC) CAFs that promotes metastasis and chemoresistance. LTBP2 exerted its oncogenic effects by interacting with integrin α6β4, which serves as a functional receptor, and thereby activating Src signaling in ESCC cells. Notably, targeting LTBP2 with specific antagonistic antibodies markedly increased the susceptibility of ESCC cells to chemotherapeutic agents. These findings highlight the pivotal role of LTBP2 as a crucial mediator of CAF-induced cancer cell aggression and introduce it as a promising target to enhance chemotherapeutic efficacy in ESCC. SIGNIFICANCE: CAF-secreted LTBP2 binds integrin α6β4 and activates Src signaling to drive metastasis and chemoresistance in esophageal cancer, highlighting LTBP2 as a key regulator of CAF-mediated tumor progression that can be therapeutically targeted.