{
  "abstract": "Background As key constituents of cellular sphingolipid pools, sphingomyelin (SM) and ceramide (CER) are central to the regulation of cancer cell death and survival. The metabolic flux between these two lipids is a vital component of the cellular stress response, yet the underlying regulatory mechanisms in cancer remain elusive. Acid sphingomyelinase (SMPD1) facilitates the conversion of SM to CER, functioning as a key enzymatic driver of CER-mediated signalling.Objectives Herein, we aim to evaluate the role of SMPD1-driven sphingolipid metabolism in pancreatic carcinogenesis.Design A targeted quantitative analysis of the plasma metabolome was conducted involving patients with pancreatic ductal adenocarcinoma (PDAC, n=202) and matched control subjects (n=204). Multiplex immunohistochemistry was performed on resected PDAC (n=122) to identify expression of SMPD1 with tumour and immune cell markers. CRISPR/Cas9 driven Smpd1-deleted murine cell lines were generated and subsequently assessed for their carcinogenic potential in vitro. The effects of Smpd1 deletion on tumour formation were evaluated using both syngeneic orthotopic and metastatic murine models.Results Here, we demonstrate that tumour cell-autonomous expression of SMPD1, in pancreatic ductal adenocarcinoma (PDAC), is associated with poorer patients’ outcomes. Smpd1 ablation in murine PDAC cells resulted in reduced proliferation and migration in vitro and decreased metastases and tumour burden in vivo. Integrated transcriptomic, metabolomic and proteomic studies revealed that SMPD1 abrogation impairs KrasG12D oncogenic signalling and, thus, reduces tumour burden. Reduced plasma membrane interaction of KrasG12D was associated with SMPD1-dependent sphingolipid metabolism. Notably, the SMPD1 inhibitor (ARC39) potently synergised with the KrasG12D inhibitor (MRTX1133).Conclusion In summary, SMPD1 regulated plasma membrane sequestration of Kras G12D represents a potential therapeutic target within the Kras signalling pathway for intractable PDAC.",
  "authors": [
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany",
        "Botton-Champalimaud Pancreatic Cancer Centre, Lisbon, Portugal"
      ],
      "name": "Ahmed Alnatsha"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany"
      ],
      "name": "Jianying Xu"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany"
      ],
      "name": "Tahib Habshi"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany",
        "Department of Gastroenterology, Capital Medical University",
        "State Key Laboratory for Digestive Health, National Clinical Center for Digestive Diseases, Beijing, People's Republic of China"
      ],
      "name": "Qi Li"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany"
      ],
      "name": "Klea Rickú"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany"
      ],
      "name": "Prince Allawadhi"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany"
      ],
      "name": "Didem Saka"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany"
      ],
      "name": "Ruoxan Dai"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany"
      ],
      "name": "Yuxing Xue"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany"
      ],
      "name": "Hang Nguyen"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany"
      ],
      "name": "Helena Stadler"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany"
      ],
      "name": "Theresa Weltermann"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany"
      ],
      "name": "Quan Zhou"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany"
      ],
      "name": "Nicole Schreiner"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany"
      ],
      "name": "Yonggan Xue"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany"
      ],
      "name": "Victoria Rittinghausen"
    },
    {
      "affiliations": [
        "Institute of Pathology, LMU University Hospital, Munich, Germany",
        "InnsPath, Tirol Klinikum, Innsbruck, Austria"
      ],
      "name": "Steffen Ormanns"
    },
    {
      "affiliations": [
        "Institute of Pathology, LMU University Hospital, Munich, Germany",
        "Bavarian Center for Cancer Research (BZKF), Munich, Germany",
        "Comprehensive Cancer Center, Munich, Germany",
        "German Cancer Consortium (DKTK), Munich Site, Munich, Germany"
      ],
      "name": "Fredrick Klauschen"
    },
    {
      "affiliations": [
        "Bavarian Center for Cancer Research (BZKF), Munich, Germany",
        "Comprehensive Cancer Center, Munich, Germany",
        "German Cancer Consortium (DKTK), Munich Site, Munich, Germany",
        "Department of Medicine III, LMU University Hospital, Munich, Germany"
      ],
      "name": "Danmei Zhang"
    },
    {
      "affiliations": [
        "Bavarian Center for Cancer Research (BZKF), Munich, Germany",
        "Comprehensive Cancer Center, Munich, Germany",
        "German Cancer Consortium (DKTK), Munich Site, Munich, Germany",
        "Department of Medicine III, LMU University Hospital, Munich, Germany",
        "Department of Hematology and Oncology, München Klinik Neuperlach, Munich, Germany"
      ],
      "name": "Stefan Böck"
    },
    {
      "affiliations": [
        "Chair of Applied Physics, Molecular physics of life and Center for NanoScience, Faculty of Physics, Ludwig-Maximilians-University, Martinsried, Germany"
      ],
      "name": "Martin Benoit"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany",
        "Bavarian Center for Cancer Research (BZKF), Munich, Germany",
        "Comprehensive Cancer Center, Munich, Germany",
        "German Cancer Consortium (DKTK), Munich Site, Munich, Germany"
      ],
      "name": "Najib Ben Khaled"
    },
    {
      "affiliations": [
        "Protein Analysis Unit (ZfP), Faculty of Medicine, Biomedical Center Munich (BMC), Ludwig Maximilians University, Munich, Germany",
        "Faculty of Medicine, Department of Molecular Biology, Faculty of Medicine, Department of Molecular Biology, Biomedical Center Munich (BMC), Ludwig-Maximilians Universität München (LMU), Munich, Germany"
      ],
      "name": "Shibojyoti Lahiri"
    },
    {
      "affiliations": [
        "Protein Analysis Unit (ZfP), Faculty of Medicine, Biomedical Center Munich (BMC), Ludwig Maximilians University, Munich, Germany",
        "Faculty of Medicine, Department of Molecular Biology, Faculty of Medicine, Department of Molecular Biology, Biomedical Center Munich (BMC), Ludwig-Maximilians Universität München (LMU), Munich, Germany"
      ],
      "name": "Axel Imhof"
    },
    {
      "affiliations": [
        "Plant Development, Ludwig-Maximilians-University Munich, Planegg-Martinsried, Munich, Germany"
      ],
      "name": "Andreas Klingl"
    },
    {
      "affiliations": [
        "Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-S.A.S. Nagar, Mohali, India"
      ],
      "name": "Anjali Jaiswal"
    },
    {
      "affiliations": [
        "Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-S.A.S. Nagar, Mohali, India"
      ],
      "name": "Girija P Sahoo"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany",
        "Institute of Tumor Immunology, Martin-Luther-University, Halle-Wittenberg, Halle, Germany"
      ],
      "name": "Ivonne Regel"
    },
    {
      "affiliations": [
        "Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany",
        "Institute for Translational Cancer Research (TranslaTUM), School of Medicine, TU Munich, Munich, Germany"
      ],
      "name": "Sebastian Mueller"
    },
    {
      "affiliations": [
        "Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany",
        "Institute for Translational Cancer Research (TranslaTUM), School of Medicine, TU Munich, Munich, Germany"
      ],
      "name": "Rupert Öllinger"
    },
    {
      "affiliations": [
        "Bavarian Center for Cancer Research (BZKF), Munich, Germany",
        "Comprehensive Cancer Center, Munich, Germany",
        "German Cancer Consortium (DKTK), Munich Site, Munich, Germany",
        "Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany",
        "Institute for Translational Cancer Research (TranslaTUM), School of Medicine, TU Munich, Munich, Germany"
      ],
      "name": "Roland Rad"
    },
    {
      "affiliations": [
        "Bavarian Center for Cancer Research (BZKF), Munich, Germany",
        "Comprehensive Cancer Center, Munich, Germany",
        "German Cancer Consortium (DKTK), Munich Site, Munich, Germany",
        "Department of Radiation Oncology, LMU University Hospital, Munich, Germany"
      ],
      "name": "Claus Belka"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany",
        "Bavarian Center for Cancer Research (BZKF), Munich, Germany",
        "Comprehensive Cancer Center, Munich, Germany",
        "German Cancer Consortium (DKTK), Munich Site, Munich, Germany"
      ],
      "name": "Tanja Bange"
    },
    {
      "affiliations": [
        "Bavarian Center for Cancer Research (BZKF), Munich, Germany",
        "Comprehensive Cancer Center, Munich, Germany",
        "German Cancer Consortium (DKTK), Munich Site, Munich, Germany",
        "Department of Radiation Oncology, LMU University Hospital, Munich, Germany"
      ],
      "name": "Kirsten Lauber"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany",
        "Bavarian Center for Cancer Research (BZKF), Munich, Germany",
        "Comprehensive Cancer Center, Munich, Germany",
        "German Cancer Consortium (DKTK), Munich Site, Munich, Germany"
      ],
      "name": "Julia Mayerle"
    },
    {
      "affiliations": [
        "Department of Medicine II, LMU University Hospital, Munich, Germany",
        "Bavarian Center for Cancer Research (BZKF), Munich, Germany",
        "Comprehensive Cancer Center, Munich, Germany",
        "German Cancer Consortium (DKTK), Munich Site, Munich, Germany",
        "Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-S.A.S. Nagar, Mohali, India"
      ],
      "name": "Ujjwal M Mahajan"
    }
  ],
  "title": "Dysregulated sphingolipid metabolismdrives pancreatic carcinogenesis through plasma membrane Kras enrichment",
  "uid": "4703bcc2-690e-5a9c-ae6d-917af71b1f60"
}