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

Yihui Chen; Riccardo Ballarò; Marta Sans; Fredrik Ivar Thege; Mingxin Zuo; Rongzhang Dou; Jimin Min; Michele Yip-Schneider; J Zhang; Ranran Wu; Ehsan Irajizad; Yuki Makino; Kimal I Rajapakshe; Hamid K Rudsari; Mark W Hurd; Ricardo A León-Letelier; Hiroyuki Katayama; Edwin Ostrin; Jody Vykoukal; Jennifer B Dennison; Kim-Anh Do; Samir M Hanash; Robert A Wolff; Paolo A Guerrero; Michael Kim; C Max Schmidt; Anirban Maitra; Johannes F Fahrmann

doi:10.1136/gutjnl-2025-335220

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

Gut. 2025 Apr 23:gutjnl-2025-335220. doi: 10.1136/gutjnl-2025-335220. Online ahead of print.

Authors

Yihui Chen^#¹, Riccardo Ballarò^#^{1

2

3}, Marta Sans^#^{2

3}, Fredrik Ivar Thege^{2

3}, Mingxin Zuo¹, Rongzhang Dou¹, Jimin Min^{2

3}, Michele Yip-Schneider⁴, J Zhang⁵, Ranran Wu¹, Ehsan Irajizad⁶, Yuki Makino^{2

3}, Kimal I Rajapakshe^{2

3}, Hamid K Rudsari⁶, Mark W Hurd³, Ricardo A León-Letelier¹, Hiroyuki Katayama¹, Edwin Ostrin⁷, Jody Vykoukal¹, Jennifer B Dennison¹, Kim-Anh Do⁶, Samir M Hanash¹, Robert A Wolff⁸, Paolo A Guerrero^{2

3}, Michael Kim⁹, C Max Schmidt⁴, Anirban Maitra^{2

3}, Johannes F Fahrmann¹⁰

Affiliations

¹ Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
² Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
³ Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁴ Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁵ Department of Epidemiology, Indiana University, Indianapolis, Indiana, USA.
⁶ Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁷ Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁸ Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁹ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
¹⁰ Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA JFFahrmann@mdanderson.org.

^# Contributed equally.

PMID: 40268349
DOI: 10.1136/gutjnl-2025-335220

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.

Keywords: METABOLOMICS; PANCREATIC CANCER.