Cell Reports
Volume 38, Issue 4, 25 January 2022, 110227
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Article
Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion

https://doi.org/10.1016/j.celrep.2021.110227Get rights and content
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Highlights

  • The Rho effector kinase PKN2 is a key regulator of myofibroblast phenotypes

  • PKN2KO induces a myofibroblast to inflammatory CAF switch in mouse pancreatic tumors

  • Stromal deletion of PKN2 promotes more locally invasive orthotopic pancreatic tumors

  • A PKN2KO matrisome signature predicts poor outcome in human pancreatic cancer

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.

Graphical abstract

Keywords

protein kinase N2
PKN2
Rho GTPases
pancreatic cancer
matrisome
tumour microenvironment
cancer-associated fibroblasts
CAF

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.

Cited by (0)

7

These authors contributed equally

8

Lead contact