Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) cells have a distinct dependence on de novo ornithine synthesis from glutamine via ornithine aminotransferase (OAT), which supports polyamine synthesis and is required for tumor growth. This directional OAT activity is normally largely restricted to infancy and contrasts with the reliance of most adult normal tissues and other cancer types on arginase (ARG) to generate arginine-derived ornithine, the substrate for polyamine synthesis. This dependence associates with arginine depletion in PDA tumor microenvironment, and is driven by mutant KRAS, which induces the expression of OAT and polyamine synthesis enzymes, including the rate-limiting enzyme ornithine decarboxylase-1 (ODC1). Loss of OAT, but not ARG2, largely mimics loss of ODC1, altering the transcriptional profiles in PDA cells, which in turn correlate with alterations in open chromatin states. Overall design: RNA-seq and ATAC-seq analyses of pancreatic ductal adenocarcinoma cells with single knockdown of either ornithine decarboxylase1 (ODC1), ornithine aminotransferase (OAT) or arginase2 (ARG2), using 2 distinct hairpins, as compared to Scrambled (Scr) control. Either three (RNA-seq) or two (ATAC-seq) biological replicates are presented for each hairpin.