{
  "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.",
  "authors": [
    {
      "affiliations": [
        "Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Yihui Chen"
    },
    {
      "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",
        "Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Riccardo Ballarò"
    },
    {
      "affiliations": [
        "Department of Translational Molecular Pathology, 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"
      ],
      "name": "Marta Sans"
    },
    {
      "affiliations": [
        "Department of Translational Molecular Pathology, 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"
      ],
      "name": "Fredrik Ivar Thege"
    },
    {
      "affiliations": [
        "Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Mingxin Zuo"
    },
    {
      "affiliations": [
        "Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Rongzhang Dou"
    },
    {
      "affiliations": [
        "Department of Translational Molecular Pathology, 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"
      ],
      "name": "Jimin Min"
    },
    {
      "affiliations": [
        "Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA"
      ],
      "name": "Michele Yip-Schneider"
    },
    {
      "affiliations": [
        "Department of Epidemiology, Indiana University, Indianapolis, Indiana, USA"
      ],
      "name": "J Zhang"
    },
    {
      "affiliations": [
        "Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Ranran Wu"
    },
    {
      "affiliations": [
        "Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Ehsan Irajizad"
    },
    {
      "affiliations": [
        "Department of Translational Molecular Pathology, 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"
      ],
      "name": "Yuki Makino"
    },
    {
      "affiliations": [
        "Department of Translational Molecular Pathology, 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"
      ],
      "name": "Kimal I Rajapakshe"
    },
    {
      "affiliations": [
        "Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Hamid K Rudsari"
    },
    {
      "affiliations": [
        "Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Mark W Hurd"
    },
    {
      "affiliations": [
        "Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Ricardo A León-Letelier"
    },
    {
      "affiliations": [
        "Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Hiroyuki Katayama"
    },
    {
      "affiliations": [
        "Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Edwin Ostrin"
    },
    {
      "affiliations": [
        "Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Jody Vykoukal"
    },
    {
      "affiliations": [
        "Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Jennifer B Dennison"
    },
    {
      "affiliations": [
        "Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Kim-Anh Do"
    },
    {
      "affiliations": [
        "Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Samir M Hanash"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Robert A Wolff"
    },
    {
      "affiliations": [
        "Department of Translational Molecular Pathology, 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"
      ],
      "name": "Paolo A Guerrero"
    },
    {
      "affiliations": [
        "Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Michael Kim"
    },
    {
      "affiliations": [
        "Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA"
      ],
      "name": "C Max Schmidt"
    },
    {
      "affiliations": [
        "Department of Translational Molecular Pathology, 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"
      ],
      "name": "Anirban Maitra"
    },
    {
      "affiliations": [
        "Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Johannes F Fahrmann"
    }
  ],
  "title": "Long-chain sulfatide enrichment is an actionable metabolic vulnerability in intraductal papillary mucinous neoplasm (IPMN)-associated pancreatic cancers",
  "uid": "5b06cd4d-6bf7-50bc-b859-eacdf8964776"
}