Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer

• Published in: Nature (London) Vol. 616; no. 7956; pp. 339 - 347
• Main Authors: Lee, Min-Sik, Dennis, Courtney, Naqvi, Insia, Dailey, Lucas, Lorzadeh, Alireza, Ye, George, Zaytouni, Tamara, Adler, Ashley, Hitchcock, Daniel S., Lin, Lin, Hoffman, Megan T., Bhuiyan, Aladdin M., Barth, Jaimie L., Machacek, Miranda E., Mino-Kenudson, Mari, Dougan, Stephanie K., Jadhav, Unmesh, Clish, Clary B., Kalaany, Nada Y.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.04.2023; Nature Publishing Group
• Subjects: 13; 13/105; 13/106; 13/109; 13/31; 13/44; 13/51; 13/89; 13/95; 38; 38/39; 38/44; 38/89; 38/90; 38/91; 45; 45/22; 45/90; 45/91; 59; 631/443/319/320; 631/67/1504/1713; 64; 64/60; 82; 82/29; 82/51; 96; 96/1; 96/95; Adenocarcinoma; Animals; Arginine - deficiency; Arginine - metabolism; Biocompatibility; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Chromatin; Depletion; Glutamine; Humanities and Social Sciences; Humans; K-Ras protein; Malignancy; Metabolism; Metabolites; Mice; Microenvironments; multidisciplinary; Nitrogen; Ornithine - biosynthesis; Ornithine - metabolism; Ornithine-aminotransferase; Ornithine-Oxo-Acid Transaminase - metabolism; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Plasma; Polyamines; Polyamines - metabolism; Prostate; Science; Science (multidisciplinary); Synthesis; Toxicity; Transaminases; Transcriptomes; Tumor Microenvironment; Tumors
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-023-05891-2

There is a need to develop effective therapies for pancreatic ductal adenocarcinoma (PDA), a highly lethal malignancy with increasing incidence 1 and poor prognosis 2 . Although targeting tumour metabolism has been the focus of intense investigation for more than a decade, tumour metabolic plasticity and high risk of toxicity have limited this anticancer strategy 3 , 4 . Here we use genetic and pharmacological approaches in human and mouse in vitro and in vivo models to show that PDA has a distinct dependence on de novo ornithine synthesis from glutamine. We find that this process, which is mediated through ornithine aminotransferase (OAT), supports polyamine synthesis and is required for tumour growth. This directional OAT activity is usually largely restricted to infancy and contrasts with the reliance of most adult normal tissues and other cancer types on arginine-derived ornithine for polyamine synthesis 5 , 6 . This dependency associates with arginine depletion in the PDA tumour microenvironment and is driven by mutant KRAS. Activated KRAS induces the expression of OAT and polyamine synthesis enzymes, leading to alterations in the transcriptome and open chromatin landscape in PDA tumour cells. The distinct dependence of PDA, but not normal tissue, on OAT-mediated de novo ornithine synthesis provides an attractive therapeutic window for treating patients with pancreatic cancer with minimal toxicity. Pancreatic ductal adenocarcinoma cells show a specific dependency on ornithine aminotransferase-mediated ornithine synthesis from glutamine, providing an opportunity to develop targeted therapies with minimal toxicity for this cancer.