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
  • 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 [email protected].
  • # 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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