Secretory mucin 5AC promotes neoplastic progression by augmenting KLF4-mediated pancreatic cancer cell stemness
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ABSTRACT: Pancreatic cancer (PC) is the third deadliest malignancy with a dismal five-year survival rate. The KrasG12D initiator mutation, present in 95% of the PC patients, leads to the development of pancreatic intraepithelial neoplasia (PanIN). The PanIN lesions, the most common precursor lesion of PC, exhibit de novo expression of mucins, which significantly contributes to PC pathobiology. The poor clinical outcome of PC warrants the identification of molecular player(s) that facilitate the progression of Kras-driven precursor lesions to invasive ductal carcinoma. Gel-forming mucin 5AC (MUC5AC) is one of the top differentially expressed genes in PC as compared to the normal pancreas. The expression of MUC5AC appears de-novo at PanIN-1A stage and elevates in tumor tissues, while remaining absent in the normal pancreas. To delineate the mechanistic contribution of Muc5ac in PC pathology, we genetically depleted Muc5ac in an autochthonous murine model (KrasG12D; Pdx-1cre, KC), which mirrors the early stages of PC. The onset of neoplastic growth and the progression of low-grade to high-grade PanIN lesions were significantly delayed in Muc5ac knockout (KrasG12D; Muc5ac-/-; Pdx-1cre, KCM) animals. We utilized high-throughput RNA seq. analysis to investigate the downstream molecular targets of Muc5ac-associated PC progression. Our study demonstrated that knockout of Muc5ac led to a significant decline in the genes associated with cancer stem cell (CSC) maintenance and epithelial-to-mesenchymal transition (EMT). The contribution of MUC5AC in CSC maintenance was validated via in vitro experiments, and tumor formation frequency using limiting dilution assay upon subcutaneous administration.
ORGANISM(S): Mus musculus
PROVIDER: GSE160029 | GEO | 2020/10/25
REPOSITORIES: GEO
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