Macrophage-secreted MMP9 induces mesenchymal transition in pancreatic cancer cells via PAR1 activation

Abstract

Purpose Targeting tumor-infiltrating macrophages limits progression and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma (PDAC). Protease-activated receptor (PAR)1 drives monocyte/macrophage recruitment, and stromal ablation of PAR1 limits cancer growth and enhances gemcitabine sensitivity in experimental PDAC. However, the functional interplay between PAR1, macrophages and tumor cells remains unexplored. Here we address the PAR1-macrophage-tumor cell crosstalk and assess its contributions to tumor progression. Methods PAR1 expression and macrophage infiltration were correlated in primary PDAC biopsies using gene expression datasets and tissue microarrays. Medium transfer experiments were used to evaluate the functional consequences of macrophage-tumor cell crosstalk and to assess the contribution of PAR1 to the observed responses. PAR1 cleavage assays were used to identify a macrophage-secreted PAR1 agonist, and the effects of candidate proteases were assessed in medium transfer experiments with specific inhibitors and/or recombinant agonist. Results PAR1 expression correlates with macrophage infiltration in primary PDACs, and macrophages induce mesenchymal transition of PDAC cells through PAR1 activation. Protease profiling identified macrophage-secreted matrix metalloprotease 9 (MMP9) as the relevant PAR1 agonist in PDAC. PAR1 and/or MMP9 inhibition limited macrophage-driven mesenchymal transition. Likewise, preventing mesenchymal transition by silencing ZEB1 or by pharmacological inhibition of the MMP9/ PAR1 axis significantly reduced the ability of tumor cells to survive the anti-tumor activities of macrophages. Conclusion Macrophages secrete MMP9, which acts upon PDAC cell PAR1 to induce mesenchymal transition. This macrophage-induced mesenchymal transition supports the tumor-promoting role of macrophage influx, explaining the dichotomous contributions of these immune cells to tumor growth.

Integrated transcriptional analysis reveals macrophage heterogeneity and tumor-macrophage interactions in the progression of pancreatic ductal adenocarcinoma

“…According to the pseudotime cell trajectory, we identi ed both in ammatory monocytes and tissue-resident macrophages as the potential sources of TAMs by trajectory analysis. TAMs compose essential compartment of the cancer-immune microenvironment and play critical roles in the regulation of tumor progression [39,40]. An in-depth understanding of the ontogeny of TAMs could facilitate therapeutic intervention.…”

Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Origin, Polarization, Function, and Reprogramming

“…Especially, pancreatic tumor cell migration rate can be enhanced through TAMs regulating the expression of ADAM8 and MMP9, conductive to breach the basement membrane and accrete the invasiveness ( Puolakkainen et al, 2014 ). Notably, MMP9 is an essential factor, which enhances the degradation of the extracellular matrix protein laminin, as a major component of blood vessels, which directly manipulates the disintegration of the vessel wall for extravasation ( Knapinska et al, 2017 ; Tekin et al, 2020 ). Likewise, MMP9 overproduction can be induced by CAF-derived IL-33 via the IL-33–ST2–NF-κB–MMP9 axis ( Andersson et al, 2018 ).…”

Identification of Prognostic Stromal-Immune Score–Based Genes in Hepatocellular Carcinoma Microenvironment

“…Finally, by using the LASSO algorithm ( Supplementary Figure 3A ), we identified seven TME-related genes. Of the seven genes identified, high levels of GDF10 and MMP9 showed a negative correlation to OS, which has been reported to be involved in carcinogenesis and the development of various cancers ( Chang et al, 2017 ; Reggiani et al, 2017 ; Tekin et al, 2020a ). We further correlated the degree of infiltration of six immune cell types with the expression of GDF10 and MMP9 by using TIMER algorithm.…”