Cell Reports (Jan 2022)
Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion
- Elizabeth R. Murray,
- Shinelle Menezes,
- Jack C. Henry,
- Josie L. Williams,
- Lorena Alba-Castellón,
- Priththivika Baskaran,
- Ivan Quétier,
- Ami Desai,
- Jacqueline J.T. 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 J.M. Cameron
Affiliations
- Elizabeth R. Murray
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Shinelle Menezes
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Jack C. Henry
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Josie L. Williams
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Lorena Alba-Castellón
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Priththivika Baskaran
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Ivan Quétier
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Ami Desai
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Jacqueline J.T. Marshall
- Protein Phosphorylation Laboratory, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
- Ian Rosewell
- Transgenic Services, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
- Marianthi Tatari
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Vinothini Rajeeve
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Faraz Khan
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Jun Wang
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Panoraia Kotantaki
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Eleanor J. Tyler
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Namrata Singh
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Claire S. Reader
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Edward P. Carter
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Kairbaan Hodivala-Dilke
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Richard P. Grose
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Hemant M. Kocher
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK; Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, Whitechapel, London E1 1BB, UK
- Nuria Gavara
- Unitat de Biofísica i Bioenginyeria, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain
- Oliver Pearce
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Pedro Cutillas
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- John F. Marshall
- Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
- Angus J.M. Cameron
- Kinase Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK; Corresponding author
- Journal volume & issue
-
Vol. 38,
no. 4
p. 110227
Abstract
Summary: 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.
