Long-chain sulfatide enrichment is an actionable metabolic vulnerability in intraductal papillary mucinous neoplasm (IPMN)-associated pancreatic cancers.

Authors

Chen Y, Ballarò R, Sans M, Thege FI, Zuo M, Dou R, Min J, Yip-Schneider M, Zhang J, Wu R, Irajizad E, Makino Y, Rajapakshe KI, Rudsari HK, Hurd MW, León-Letelier RA, Katayama H, Ostrin E, Vykoukal J, Dennison JB, ...show more Do KA, Hanash SM, Wolff RA, Guerrero PA, Kim M, Schmidt CM, Maitra A, Fahrmann JF

Affiliations

• Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
• Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
• Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA.
• Department of Epidemiology, Indiana University, Indianapolis, Indiana, USA.
• Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
• Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
• Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
• Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
• Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
• Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA JFFahrmann@mdanderson.org.

Abstract

BACKGROUND: We conducted an integrated cross-species spatial assessment of transcriptomic and metabolomic alterations associated with progression of intraductal papillary mucinous neoplasms (IPMNs), which are bona fide cystic precursors of pancreatic ductal adenocarcinoma (PDAC).

OBJECTIVE: We aimed to uncover biochemical and molecular drivers that underlie malignant progression of IPMNs to PDAC.

DESIGN: Matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry (MS)-based spatial imaging and Visium spatial transcriptomics (ST) was performed on human resected IPMN/PDAC tissues (n=23) as well as pancreata from a mutant Kras;Gnas mouse model of IPMN/PDAC. Functional studies in murine IPMN/PDAC-derived Kras;Gnas cells were performed using CRISPR/cas9 technology, small interfering RNAs, and pharmacological inhibition.

RESULTS: MALDI-MS analyses of patient tissues revealed long-chain hydroxylated sulfatides to be selectively enriched in the neoplastic epithelium of IPMN/PDAC. Integrated ST analyses showed cognate transcripts involved in sulfatide biosynthesis, including UGT8, Gal3St1, and FA2H, to co-localise with areas of sulfatide enrichment. Genetic knockout or pharmacological inhibition of UGT8 in Kras;Gnas IPMN/PDAC cells decreased protein expression of FA2H and Gal3ST1 with consequent alterations in mitochondrial morphology and reduced mitochondrial respiration. Small molecule inhibition of UGT8 elicited anticancer effects via ceramide-mediated compensatory mitophagy and activation of intrinsic apoptosis pathways. In vivo, UGT8 inhibition suppressed tumour growth in allograft models of murine IPMN/PDAC cells derived from Kras;Gnas and Kras;Tp53;Gnas mice.

CONCLUSION: Our work identifies enhanced sulfatide metabolism as an early metabolic alteration in cystic precancerous lesions of the pancreas that persists through invasive neoplasia and a potential actionable vulnerability in IPMN-derived PDAC.