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SERPINB3-MYC axis induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancer

  1. Author:
    Ohara, Yuuki
    Tang, Wei
    Liu, Huaitian
    Yang, Shouhui
    Dorsey, Tiffany H
    Cawley, Helen
    Moreno, Paloma
    Chari,Raj
    Guest,Mary
    Azizian, Azadeh
    Gaedcke, Jochen
    Ghadimi, Michael
    Hanna, Nader
    Ambs, Stefan
    Hussain, S Perwez

  2. Author Address

    1Pancreatic Cancer Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: yuuki.oohara.1196@gmail.com. 2Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Data Science & Artificial Intelligence, R&D, AstraZeneca, Gaithersburg, MD 20878, USA. 3Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. 4Pancreatic Cancer Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. 5Genome Modification Core, Laboratory Animal Sciences Program, Frederick National Lab for Cancer Research, Frederick, MD 21701, USA. 6Städtisches Klinikum Karlsruhe, Moltkestraße 90, 76133 Karlsruhe, Germany. 7Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany. 8Division of General & Oncologic Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. 9Pancreatic Cancer Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: hussainp@mail.nih.gov.
    1. Year: 2023
    2. Date: Nov 18
    3. Epub Date: 2023 11 18
  2. Journal: Cell Reports
    1. 42
    2. 12
    3. Pages: 113434
  4. Type of Article: Article
  5. Article Number: 113434
  1. Abstract:

    Pancreatic ductal adenocarcinoma (PDAC) exhibits distinct molecular subtypes: classical/progenitor and basal-like/squamous. Our study aimed to identify genes contributing to the development of the basal-like/squamous subtype, known for its aggressiveness. Transcriptome analyses revealed consistent upregulation of SERPINB3 in basal-like/squamous PDAC, correlating with reduced patient survival. SERPINB3 transgene expression in PDAC cells enhanced in vitro invasion and promoted lung metastasis in a mouse PDAC xenograft model. Metabolome analyses unveiled a metabolic signature linked to both SERPINB3 and the basal-like/squamous subtype, characterized by heightened carnitine/acylcarnitine and amino acid metabolism, associated with poor prognosis in patients with PDAC and elevated cellular invasiveness. Further analysis uncovered that SERPINB3 inhibited the cysteine protease calpain, a key enzyme in the MYC degradation pathway, and drove basal-like/squamous subtype and associated metabolic reprogramming through MYC activation. Our findings indicate that the SERPINB3-MYC axis induces the basal-like/squamous subtype, proposing SERPINB3 as a potential diagnostic and therapeutic target for this variant. Copyright © 2023. Published by Elsevier Inc.

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External Sources

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  2. DOI: 10.1016/j.celrep.2023.113434
  3. PMID: 37980563
  4. PII : S2211-1247(23)01446-8

Library Notes

  1. Fiscal Year: FY2023-2024
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