Adipogenic Transdifferentiation Reprograms EMT high PDAC Cells into a Post mitotic Adipocyte like State and Limits Metastasis
To define the epigenomic and transcriptional basis of observed phenotypic and metabolic changes of AsPC-1 cells after adipogenesis induction, we performed assay for transposase accessible chromatin with high throughput sequencing (ATAC-seq) and transcriptomic sequencing (RNA-seq) in control and induced AsPC-1 cells. ATAC-seq revealed a genome-wide decrease in chromatin accessibility after induction. TOBIAS based differential footprinting analysis showed higher binding activity of transcriptional factors such as sterol regulatory element binding protein 1 (SRBP1), p53, p63 and p73. RNA-seq showed a global reduction in gene expression, a hallmark of post mitotic states. MMPs were broadly downregulated, suggesting diminished invasive potential. Adipogenesis markers FABP4 and CEBPB showed significant upregulation. Unsupervised clustering of lineage markers demonstrated a clear phenotypic shift: untreated cells grouped with mesenchymal phenotype, whereas induced cells clustered with mature adipocyte signatures. GO term analysis of RNA-seq indicated upregulation of apoptosis, cell adhesion and lipid metabolism pathways and downregulation of cell proliferation, TGF-beta response and mesenchymal differentiation programs. Collectively, these multi-omics data indicate that AsPC-1 cells transition from an EMT-high status to transcriptionally quiescent, adipocyte-like cells with reduced cell proliferative and metastatic capacities. We further sequenced the tumor samples to comprehensively elucidate the transcriptomic alterations induced by adipogenic transdifferentiation in vivo. The transdifferentiated group displayed significantly decreased expression of MMPs, along with an enhanced adipocyte gene signature.