2. Academic Validation
  3. SERPINB3-MYC axis induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancer

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

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: yuuki.oohara.1196@gmail.com.
  • 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: hussainp@mail.nih.gov.
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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