Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion
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Elizabeth R Murray Shinelle Menezes Jack C Henry Josie L Williams Lorena Alba-Castellón Priththivika Baskaran Ivan Quétier Ami Desai Jacqui Marshall Ian Rosewell Marianthi Tatari Vinothini Rajeeve Faraz Khan Jun Wang Panoraia Kotantaki Eleanor J Tyler Namrata Singh Claire S Reader Edward P Carter Kairbaan Hodivala-Dilke Richard P Grose Hemant M Kocher Nuria Gavara Oliver Pearce Pedro Cutillas John F Marshall Angus JM Cameron Toggle all authors (27)
Abstract
In pancreatic ductal adenocarcinoma (PDAC), differentiation of pancreatic stellate cells (PSCs) into myofibroblast-like cancer-associated fibroblasts (CAFs) can both promote and suppress tumor progression. Here, we show that the Rho effector protein kinase N2 (PKN2) is critical for PSC myofibroblast differentiation. Loss of PKN2 is associated with reduced PSC proliferation, contractility, and alpha-smooth muscle actin (α-SMA) stress fibers. In spheroid co-cultures with PDAC cells, loss of PKN2 prevents PSC invasion but, counter-intuitively, promotes invasive cancer cell outgrowth. PKN2 deletion induces a myofibroblast to inflammatory CAF switch in the PSC matrisome signature both in vitro and in vivo. Further, deletion of PKN2 in the pancreatic stroma induces more locally invasive, orthotopic pancreatic tumors. Finally, we demonstrate that a PKN2KO matrisome signature predicts poor outcome in pancreatic and other solid human cancers. Our data indicate that suppressing PSC myofibroblast function can limit important stromal tumor-suppressive mechanisms, while promoting a switch to a cancer-supporting CAF phenotype.
Journal details
Journal Cell Reports
Volume 38
Issue number 4
Pages 110227
Available online
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Publisher website (DOI) 10.1016/j.celrep.2021.110227
Europe PubMed Central 35081338
Pubmed 35081338
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