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

  • Cell Rep. 2023 Nov 18;42(12):113434. doi: 10.1016/j.celrep.2023.113434.
Yuuki Ohara  1 ,  Wei Tang  2 ,  Huaitian Liu  3 ,  Shouhui Yang  4 ,  Tiffany H Dorsey  3 ,  Helen Cawley  4 ,  Paloma Moreno  4 ,  Raj Chari  5 ,  Mary R Guest  5 ,  Azadeh Azizian  6 ,  Jochen Gaedcke  6 ,  Michael Ghadimi  7 ,  Nader Hanna  8 ,  Stefan Ambs  3 ,  S Perwez Hussain  9
Affiliations
  • 1. Pancreatic Cancer Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: [email protected].
  • 2. Laboratory 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.
  • 3. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 4. Pancreatic Cancer Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 5. Genome Modification Core, Laboratory Animal Sciences Program, Frederick National Lab for Cancer Research, Frederick, MD 21701, USA.
  • 6. Städtisches Klinikum Karlsruhe, Moltkestraße 90, 76133 Karlsruhe, Germany.
  • 7. Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.
  • 8. Division of General & Oncologic Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • 9. Pancreatic Cancer Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: [email protected].
PMID: 37980563 DOI: 10.1016/j.celrep.2023.113434
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.

Keywords
BBOX1; CP: Cancer; CP: Metabolism; MYC; SERPINB3/SCCA1; amino acid; calpain; carnitine/acylcarnitine; metabolism; molecular subtype; pancreatic ductal adenocarcinoma; serine/cysteine proteinase inhibitor family B member 3.
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