Abstract
SummaryIn 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.
Highlights
Fibroblasts play critical roles in mammalian development, homeostasis, and wound repair, where they dynamically regulate tissue structure through paracrine signaling and modulation of the extracellular matrix and connective tissue
In pancreatic ductal adenocarcinoma (PDAC), resident pancreatic stellate cells (PSCs) become activated in response to tumor-derived paracrine signals, such as transforming growth factor-b (TGF-b), sonic hedgehog (Shh), and platelet-derived growth factor (PDGF), resulting in desmoplastic, hypovascular tumors, which respond poorly to therapy
protein kinase N2 (PKN2) regulates PSC growth and TGF-b1-induced myofibroblast differentiation To generate a model in which the role of PKN2 in PSC function could be assessed, inducible PKN2 knockout (KO) PSCs were derived from the pancreas of a Rosa26CreERT2+/WT PKN2fl/fl mouse by Histodenz cushion centrifugation (Apte et al, 1998; Bachem et al, 1998; Vonlaufen et al, 2010)
Summary
Fibroblasts play critical roles in mammalian development, homeostasis, and wound repair, where they dynamically regulate tissue structure through paracrine signaling and modulation of the extracellular matrix and connective tissue. During tissue remodeling and in response to inflammation, fibroblasts become activated into contractile alpha-smooth muscle actin (a-SMA)positive myofibroblasts, which show enhanced extracellular matrix (ECM) deposition and matrix-remodeling activities. The predominant resident fibroblast cell type is the pancreatic stellate cell (PSC), characterized by lipid and vitamin storage droplets and intermediate filament expression (Apte et al, 1998; Froeling et al, 2011). In pancreatic ductal adenocarcinoma (PDAC), resident PSCs become activated in response to tumor-derived paracrine signals, such as transforming growth factor-b (TGF-b), sonic hedgehog (Shh), and platelet-derived growth factor (PDGF), resulting in desmoplastic, hypovascular tumors, which respond poorly to therapy. The reciprocal interaction between malignant PDAC cells and PSCs has attracted increasing attention clinically, and identifying targets to modify PSC function is a priority (Froeling and Kocher, 2015; Kocher et al, 2020)
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