VDR Activation Suppresses Pancreatic Cancer Metastasis Through Inhibition of the ERK Signaling Pathway

The vitamin D receptor (VDR) has been implicated in tumor progression, but its functional role in pancreatic ductal adenocarcinoma (PDAC) metastasis remains unclear. Here, using pharmacological modulation, gain- and loss-of-function approaches, transcriptomic profiling, and an experimental lung colonization model, we demonstrate that VDR acts as a suppressor of PDAC metastasis. Pharmacological activation of VDR by calcipotriol did not affect tumor cell proliferation but markedly inhibited the migratory and invasive capacities of multiple PDAC cell lines. In contrast, genetic deletion or pharmacological inhibition of VDR significantly enhanced metastatic phenotypes. To investigate the underlying mechanisms, we performed RNA sequencing on PDAC cells with differential VDR expression following calcipotriol treatment. Pathway enrichment analysis identified MAPK/ERK signaling as one of the most prominently altered pathways upon VDR activation. Functional studies further demonstrated that ERK inhibition abrogated the pro-metastatic effects induced by VDR loss or inhibition. In vivo lung colonization assays confirmed that VDR deficiency markedly promoted pulmonary metastatic colonization. Collectively, these findings identify VDR as a critical suppressor of PDAC cell metastatic colonization and reveal a previously unrecognized VDR–ERK regulatory axis that may represent a potential therapeutic target for limiting metastatic progression in pancreatic cancer.