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-DilkeRichard P Grose, Hemant M Kocher, Nuria Gavara, Oliver Pearce, Pedro Cutillas, John F Marshall, Angus J M Cameron

Research output: Contribution to journalArticlepeer-review

38 Citations (SciVal)

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.

Original languageEnglish
Pages (from-to)110227
JournalCell Reports
Volume38
Issue number4
DOIs
Publication statusPublished - 25 Jan 2022

Bibliographical note

This research was funded by Worldwide Cancer Research/Pancreatic Cancer Research Fund (18-0713), Pancreatic Cancer UK (PCUK2015_A26_Cameron), the Academy of Medical Sciences (SBF001\1004), The Royal Society (RG140568), Barts Charity (MGU0605), and Cancer Research UK Center Grants to Barts Cancer Institute (C355/A25137) and the City of London Centre (C7893/A26233); E.R.M. and J.C.H. were funded by Cancer Research UK studentships (C16420/A20916 and C355/A29277) and the Rosetrees Trust (M483). J.L.W. is supported by a BBSRC/AstraZeneca iCASE/LIDo studentship, and P.B. was supported by an MRC studentship to QMUL.

Data and code availability

RNA-sequencing data has been deposited at GEO and are publicly available as of the date of publication. Accession numbers are listed in the key resources table. Western blot and microscopy data are available upon request from the lead contact. This paper also analyzes existing, publicly available data. These accession numbers for the datasets are listed in the key resources table.


All original code has been deposited at Github and is publicly available as of the date of publication. DOIs are listed in the key resources table.


Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Keywords

  • Animals
  • Humans
  • Mice
  • Neoplasm Invasiveness/pathology
  • Pancreatic Neoplasms/pathology
  • Pancreatic Stellate Cells/metabolism
  • Phenotype
  • Protein Kinase C/metabolism
  • Tumor Microenvironment/physiology

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