Cell reports · 2023
SERPINB3-MYC axis induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancer.
СтатьяResearch Support, N.I.H., IntramuralНазвание и аннотация: Перевод пока не подготовлен
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Ohara Yuuki, Tang Wei, Liu Huaitian, Yang Shouhui, Dorsey Tiffany H, Cawley Helen, Moreno Paloma, Chari Raj, Guest Mary R, Azizian Azadeh, Gaedcke Jochen, Ghadimi Michael, Hanna Nader, Ambs Stefan, Hussain S Perwez
Аннотация
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.