Adipogenic transdifferentiation reprograms EMT-high PDAC cells into a post-mitotic adipocyte-like state and limits metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is a notoriously lethal malignancy with high epithelial-mesenchymal transition (EMT) baseline. EMT is associated with enhanced cell plasticity and contributes to tumor adaption and evolution. EMT programs fuel PDAC invasion, metastasis, and treatment resistance, but directly targeting EMT has yielded limited clinical benefits. Transdifferentiation therapy that exploits cell plasticity and redirects malignant cell fate offers an orthogonal approach beyond pathway inhibition. To validate the feasibility of transdifferentiation in epithelial malignancies such as PDAC, we applied an adipogenesis protocol in seven human PDAC cell lines and distinguished AsPC-1 with intensified adipocyte features (intracellular lipid droplets accumulation, elevated adiponectin, CEBPA, PPARG, FABP4 expression). AsPC-1 was converted into adipocyte-like, post-mitotic cells with lipometabolic (enhanced adiponectin secretion and lipolysis) and phenotypic reprogramming (proliferation inhibition, G1 cell cycle arrest, and EMT key transcription factors downregulation). Multi-omics showed global chromatin compaction and transcriptome-wide repression of EMT and metastatic programs in induced AsPC-1 cells, with suppressed MMPs and TGF-β, indicating diminished metastatic potential. Therefore, we further evaluated the possibility of clinical translation by murine orthotopic and hepatic metastasis models, finding adipogenesis induction reduced primary tumor burden and slowed metastatic progression. The adipocyte-like phenotype in vivo was sustained through one-month observation period following induction drug withdrawal. This study establishes a plasticity-oriented "convert-instead-of-kill" strategy for EMT-high PDAC, suggesting a potential for future studies to investigate rational combinations (e.g., transdifferentiation therapy combined with targeted or immunotherapy) to exploit lineage conversion.