Notch1 supports proliferation and bioenergetic activity in a pancreatic neuroendocrine neoplasm cell line.

چکیده اصلی

BACKGROUND: Pancreatic neuroendocrine neoplasms (PNENs) arise from neuroendocrine cells of the pancreas. Therapeutic options are limited for patients with advanced disease and the molecular mechanisms that drive PNEN progression remain elusive. The Notch pathway regulates cell fate, proliferation, cell-cell communication, and survival in multicellular organisms. Dysregulation of one pathway member, Notch1, has been linked to the development and growth of several cancers; however, the role of Notch1 signaling in PNENs is not defined. METHODS: Notch1 expression was evaluated in normal adult pancreas and PNENs using publicly available single-cell RNA sequencing data from the Human Protein Atlas and immunohistochemistry on PNEN tissue microarrays. A CRISPR/Cas9-mediated knockout of Notch1 was generated in a PNEN cell line ('BON'). The functional impact of Notch1 loss was assessed through proliferation assays, cell cycle analysis, bulk transcriptomics, and Seahorse metabolic flux assays. In vivo tumor growth was evaluated using subcutaneous xenografts, and global proteomic profiling was performed on resected tumors. RESULTS: Notch1 was found to be absent in normal adult pancreatic neuroendocrine cells but was re-expressed in 39-45% of primary and metastatic PNENs. Genetic deletion of Notch1 significantly reduced PNEN cell proliferation in both 2D and 3D conditions, induced G1 cell cycle arrest, and slowed xenograft tumor growth. We also found that Notch1 regulates proliferation and cellular bioenergetic pathways in PNEN cells. CONCLUSIONS: Our findings reveal a role for Notch1 in supporting proliferation and bioenergetics in a PNEN cell line, providing new insights into its potential oncogenic function and contribution to PNEN pathobiology.

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