M2‐phenotype tumour‐associated macrophages upregulate the expression of prognostic predictors MMP14 and INHBA in pancreatic cancer

Abstract

Pancreatic cancer is one of the most lethal gastrointestinal tumours, the most common pathological type is pancreatic adenocarcinoma (PAAD). In recent year, immune imbalanced in tumour microenvironment has been shown to play an important role in the evolution of tumours progression, and the efficacy of immunotherapy has been gradually demonstrated in clinical practice. In this study, we propose to construct an immune‐related prognostic risk model based on immune‐related genes MMP14 and INHBA expression that can assess the prognosis of pancreatic cancer patients and identify potential therapeutic targets for pancreatic cancer, to provide new ideas for the treatment of pancreatic cancer. We also investigate the correlation between macrophage infiltration and MMP14 and INHBA expression. First, the gene expression data of pancreatic cancer and normal pancreatic tissue were obtained from The Cancer Genome Atlas Program (TCGA) and The Genotype‐Tissue Expression public database (GTEx). The differentially expressed immune‐related genes between pancreatic cancer samples and normal sample were screened by R software. Secondly, univariate Cox regression analysis were used to evaluate the relationship between immune‐related genes and the prognosis of pancreatic cancer patients. A polygenic risk score model was constructed by Cox regression analysis. The prognostic nomogram was constructed, and its performance was evaluated comprehensively by internal calibration curve and C‐index. Using the risk model, each patient gets a risk score, and was divided into high‐ or low‐ risk groups. The proportion of 22 types of immune cells infiltration in pancreatic cancer samples was inferred by CIBERSOFT algorithm, correlation analysis (Pearson method) was used to analyse the correlation between the immune‐related genes and immunes cells. Then, we applied macrophage conditioned medium to culture pancreatic cancer cell line PANC1, detected the expression of MMP14 and INHBA by qRT‐PCR and Western blot methods. Knock‐down MMP14 and INHBA in PANC1 cells by transfected with shRNA lentiviruses. Detection of migration ability of pancreatic cells was done by trans‐well cell migration assay. A subcutaneous xenograft tumour model of human pancreatic cancer in nude mice was constructed. In conclusion, an immune‐related gene prognostic model was constructed, patients with high‐risk scores have poorer survival status, M2‐phenotype tumour‐associated macrophages (TAMs) up‐regulate two immune‐related genes, MMP14 and INHBA, which were used to establish the prognostic model. Knock‐down of MMP14 and INHBA inhibited invasion of pancreatic cancer.

Morphine disrupts macrophage functions even during HIV infection

“…VEGFR2 signaling increases expression and activation of enzymes that degrade the extracellular matrix, including a disintegrin and metalloproteinase domain‐containing protein 10 and MMP14, which were both increased significantly by MOR (Table S1). MMP14 is also a marker of advanced cancer disease and higher mortality when expressed by tumor‐associated macrophages 61 . Our studies suggest future examination of postmortem tissue from opioid users with HIV‐NCI to correlate macrophage expression of MMP14, and other metalloproteinases, with known markers of CNS damage.…”

“…Because we found that VEGFA‐VEGFR2 signaling was up‐regulated, we quantified MMP14, a MMP in this pathway that was increased. MMP14 breaks down collagen and activates other key MMPs such as MMP2 61 . Proteolysis degrades the extracellular matrix to facilitate cell migration.…”

“…One finding was increased VEGFA/VEGFR2 signaling, which is important for tumor cell invasion, angiogenesis, and metastasis 60 . Some studies indicate that VEGFR2 is expressed on macrophages in the context of disease processes such as tumor development 60,61 . VEGFR2 signaling increases expression and activation of enzymes that degrade the extracellular matrix, including a disintegrin and metalloproteinase domain‐containing protein 10 and MMP14, which were both increased significantly by MOR (Table S1).…”

“…MMP14 breaks down collagen and activates other key MMPs such as MMP2. 61 Proteolysis degrades the extracellular matrix to facilitate cell migration. This could facilitate movement of HIV-infected macrophages within the CNS to disseminate viral particles, toxic viral proteins, inflammatory mediators, and ROS.…”

A new transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma

“…Macro-1 and Macro-2 showed a significantly increased M2 macrophage signature score compared to Macro-3 (Fig. 2c) and expressed typical M2 marker genes ( CD68, TGFB1, CD163 11,26-28 , TGFB2 29 , CCL18 30 , MMP14 31 , CTSD 32 , MARCO 33 and CSF1R 34 ) (Extended data Fig. 2a) suggesting that these macrophages are suppressive of the immune response and likely supporting tumor growth 13 .…”