SERPINB3-MYC axis induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancer
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 con...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723014468 |
| _version_ | 1797564981483405312 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yuuki Ohara |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T19:05:31Z |
| format | Article |
| id | doaj.art-de1d8a8b6bbd4daaa1ee9af22b193d83 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-10T19:05:31Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-de1d8a8b6bbd4daaa1ee9af22b193d832023-11-20T04:11:42ZengElsevierCell Reports2211-12472023-12-014212113434SERPINB3-MYC axis induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancerYuuki Ohara0Wei Tang1Huaitian Liu2Shouhui Yang3Tiffany H. Dorsey4Helen Cawley5Paloma Moreno6Raj Chari7Mary R. Guest8Azadeh Azizian9Jochen Gaedcke10Michael Ghadimi11Nader Hanna12Stefan Ambs13S. Perwez Hussain14Pancreatic Cancer Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Corresponding authorLaboratory 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, USALaboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAPancreatic Cancer Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USALaboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAPancreatic Cancer Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAPancreatic Cancer Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAGenome Modification Core, Laboratory Animal Sciences Program, Frederick National Lab for Cancer Research, Frederick, MD 21701, USAGenome Modification Core, Laboratory Animal Sciences Program, Frederick National Lab for Cancer Research, Frederick, MD 21701, USAStädtisches Klinikum Karlsruhe, Moltkestraße 90, 76133 Karlsruhe, GermanyStädtisches Klinikum Karlsruhe, Moltkestraße 90, 76133 Karlsruhe, GermanyDepartment of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, GermanyDivision of General & Oncologic Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USALaboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAPancreatic Cancer Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723014468CP: CancerCP: Metabolism |
| spellingShingle | 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 SERPINB3-MYC axis induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancer Cell Reports CP: Cancer CP: Metabolism |
| title | SERPINB3-MYC axis induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancer |
| title_full | SERPINB3-MYC axis induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancer |
| title_fullStr | SERPINB3-MYC axis induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancer |
| title_full_unstemmed | SERPINB3-MYC axis induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancer |
| title_short | SERPINB3-MYC axis induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancer |
| title_sort | serpinb3 myc axis induces the basal like squamous subtype and enhances disease progression in pancreatic cancer |
| topic | CP: Cancer CP: Metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723014468 |
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