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

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.
Yihui Chen # 1,  Riccardo Ballarò # 1 2 3,  Marta Sans # 2 3,  Fredrik Ivar Thege 2 3,  Mingxin Zuo 1,  Rongzhang Dou 1,  Jimin Min 2 3,  Michele Yip-Schneider 4,  J Zhang 5,  Ranran Wu 1,  Ehsan Irajizad 6,  Yuki Makino 2 3,  Kimal I Rajapakshe 2 3,  Hamid K Rudsari 6,  Mark W Hurd 3,  Ricardo A León-Letelier 1,  Hiroyuki Katayama 1,  Edwin Ostrin 7,  Jody Vykoukal 1,  Jennifer B Dennison 1,  Kim-Anh Do 6,  Samir M Hanash 1,  Robert A Wolff 8,  Paolo A Guerrero 2 3,  Michael Kim 9,  C Max Schmidt 4,  Anirban Maitra 2 3,  Johannes F Fahrmann 10
Affiliations

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.

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