SERPINB3-MYC axis induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancer
Yuuki Ohara,
Wei Tang,
Huaitian Liu,
Shouhui Yang,
Tiffany H. Dorsey,
Helen Cawley,
Paloma Moreno,
Raj Chari,
Mary R. Guest,
Azadeh Azizian,
Jochen Gaedcke,
Michael Ghadimi,
Nader Hanna,
Stefan Ambs,
S. Perwez Hussain
Affiliations
Yuuki Ohara
Pancreatic Cancer Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Corresponding author
Wei Tang
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
Huaitian Liu
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Shouhui Yang
Pancreatic Cancer Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Tiffany H. Dorsey
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Helen Cawley
Pancreatic Cancer Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Paloma Moreno
Pancreatic Cancer Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Raj Chari
Genome Modification Core, Laboratory Animal Sciences Program, Frederick National Lab for Cancer Research, Frederick, MD 21701, USA
Mary R. Guest
Genome Modification Core, Laboratory Animal Sciences Program, Frederick National Lab for Cancer Research, Frederick, MD 21701, USA
Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany
Nader Hanna
Division of General & Oncologic Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Stefan Ambs
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
S. Perwez Hussain
Pancreatic Cancer Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Corresponding author
Summary: 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.
