Abstract PR-13: Disruption of sulfatide metabolism by targeting UGT8 is an actionable metabolic vulnerability for pancreatic cancer early interception

Abstract

Abstract The existence of asymptomatic precursor lesions that are known to predate invasive pancreatic ductal adenocarcinoma (PDAC) by years provides a compelling rationale for cancer interception efforts. One such precursor is intraductal papillary mucinous neoplasm (IPMN). Using Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry (MALDI-MS) imaging of metabolites in tissue sections from resected patient IPMN cases (N=23) and from a KrasG12D/GnasR201C mouse model of IPMN, we have made a discovery of long chain hydroxylated sulfatide species as being selectively enriched in IPMN. Spatial transcriptomics analysis of serial sections from the same IPMN tissues confirmed cognate transcripts, including ceramide galactosyltransferase (CGT, also known as UGT8) and galactose-3-O-sulfotransferase (CST, also known as Gal3St1) enzymes that, respectively, catalyze the addition of galactose from UDP-galactose to ceramide and the O-sulfation of the galactose residue on galactosylceramide (GalCer), to also be highly enriched in IPMN. Functional studies using CRISPR/cas9 UGT8 knockout Kras;Gnas IPMN cells demonstrated that loss of UGT8, the key enzyme that produces the sulfatide precursor GalCer, results in attenuation of sulfatide biosynthesis and impaired mitochondrial function, as evidenced by reduced mitochondrial respiration and ATP production. These changes were met with concomitant decreases in proliferation and invasiveness, and increased susceptibility to intrinsic apoptosis. Targeting of sulfatide metabolism using a selective small molecule inhibitor of UGT8 suppressed sulfatide biosynthesis, induced ceramide-mediated compensatory mitophagy, and subsequent apoptosis in Kras;Gnas IPMN cells. In vivo, UGT8 inhibition suppressed tumor growth in an IPMN allograft model. In conclusion, our work identifies enhanced sulfatide metabolism as an early metabolic alteration in cystic pre-cancerous lesions of the pancreas that persists through invasive neoplasia and represents an actionable vulnerability for PDAC early interception. Citation Format: Riccardo Ballarò, Yihui Chen, Fredrik I Thege, Rongzhang Dou, Jimin Min, Michele Yip-Schneider, Jianjun Zhang, Ranran Wu, Ehsan Irajizad, Yuki Makino, Kimal I Rajapakshe, Mark W Hurd, Ricardo A León-Letelier, Edwin Ostrin, Jody Vykoukal, Jennifer B Dennison, Kim-Anh Do, Samir Hanash, Robert A Wolff, Paola A Guerrero, Michael P Kim, C Max Schmidt, Anirban Maitra, Johannes F Fahrmann. Disruption of sulfatide metabolism by targeting UGT8 is an actionable metabolic vulnerability for pancreatic cancer early interception [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-13.