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内容記述 |
Pancreatic ductal adenocarcinoma (PDAC) features a fibrotic tumor microenvironment that impedes drug delivery and significantly limits the successful clinical application of nanomedicines. Targeting signaling in pancreatic stellate cells (PSCs), whichdrive fibrosis via excessive secretion of extracellular matrix proteins such as collagen I, may be useful in overcoming this fibroticbarrier. The AMPK-related kinases NUAK1/2 have recently gained interest as promoters of fibrosis, but whether they play aprofibrotic role in PSCs remains unknown. Here, patient PSCs are used to assess NUAK1/2 involvement in the PDAC fibroticbarrier. Leveraging a 3D cell culture model of PDAC fibrosis, the effect of targeting NUAK1/2 on the permeability of macromolecular dextrans of various sizes, as well as physiologically relevant macromolecules, albumin and IgG, and clinical nanomedicines, Doxil and Abraxane, is investigated. NUAK1/2 inhibition is shown to diminish collagen I to enhance macromolecularpermeability, via a mechanism independent of established pathways involving transforming growth factor-β (TGFβ) andyes-associated protein (YAP). Through isoform-specific knockdown, predominant NUAK2 involvement is demonstrated.Mechanistically, actin stress fiber regulation by NUAK2 is shown to be important. Altogether, these results show in vitro thatNUAK2 promotes fibrotic signaling in PSCs and may be targeted to enhance macromolecular drug delivery in PDAC. |
