Long-chain sulfatide enrichment is an actionable metabolic vulnerability in intraductal papillary mucinous neoplasm (IPMN)-associated pancreatic cancers.
Abstract
We conducted an integrated cross-species spatial assessment of transcriptomic and metabolomic alterations associated with progression of intraductal papillary mucinous neoplasms (IPMNs), which are <i>bona fide</i> cystic precursors of pancreatic ductal adenocarcinoma (PDAC).
We aimed to uncover biochemical and molecular drivers that underlie malignant progression of IPMNs to PDAC.
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 <i>Kras;Gnas</i> mouse model of IPMN/PDAC. Functional studies in murine IPMN/PDAC-derived <i>Kras;Gnas</i> cells were performed using CRISPR/cas9 technology, small interfering RNAs, and pharmacological inhibition.
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 <i>UGT8</i>, <i>Gal3St1</i>, and <i>FA2H</i>, to co-localise with areas of sulfatide enrichment. Genetic knockout or pharmacological inhibition of UGT8 in <i>Kras;Gnas</i> 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 <i>Kras;Gnas</i> and <i>Kras;Tp53;Gnas</i> mice.
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.
EDRN PI Authors
Medline Author List
- Ballarò R
- Chen Y
- Dennison JB
- Do KA
- Dou R
- Fahrmann JF
- Guerrero PA
- Hanash SM
- Hurd MW
- Irajizad E
- Katayama H
- Kim M
- León-Letelier RA
- Maitra A
- Makino Y
- Min J
- Ostrin E
- Rajapakshe KI
- Rudsari HK
- Sans M
- Schmidt CM
- Thege FI
- Vykoukal J
- Wolff RA
- Wu R
- Yip-Schneider M
- Zhang J
- Zuo M