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Tumor-associated macrophages promote pancreatic ductal adenocarcinoma progression by inducing epithelial-to-mesenchymal transition.

ABSTRACT: In this study, we investigated the role of tumor-associated macrophages (TAMs) in the progression of pancreatic ductal adenocarcinoma (PDAC). PDAC patients with higher levels of CD68⁺ TAMs exhibited shorter overall survival. In Transwell assays, PDAC cells incubated with TAMs or conditioned media from TAM cells (TAM-CM) showed higher migration and invasion rates than controls. PET/CT scan analysis of orthotopic PDAC model mice revealed greater primary tumor growth and liver metastasis in the TAM-CM treatment group than the controls. H&E staining of liver tissues showed significantly higher numbers of metastatic nodules in the TAM-CM treatment group. Heat inactivation of TAM-CM significantly reduced Transwell migration by PDAC cells, suggesting the involvement of one or more secreted proteins in PDAC progression. Transcriptome sequencing analysis of PDAC cells treated with TAM-CM revealed significant enrichment of transforming growth factor-? (TGF-?) signaling pathway genes. Western blot and qRT-PCR analysis showed that TAM-CM enhanced PDAC migration cells by inducing epithelial-to-mesenchymal transition through the TGF-?-Smad2/3/4-Snail signaling axis. The pro-tumorigenic effects of TAMs or TAM-CM were abolished by TGF-? signaling pathway inhibitors and neutralizing TGF-? antibody. These results demonstrate that TAMs promote PDAC progression through the TGF-? signaling pathway.

SUBMITTER: Xiong C

PROVIDER: S-EPMC7906203 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Tumor-associated macrophages promote pancreatic ductal adenocarcinoma progression by inducing epithelial-to-mesenchymal transition.

Xiong Cheng C Zhu Youwei Y Xue Meilin M Jiang Yongsheng Y Zhong Yiming Y Jiang Lingxi L Shi Minmin M Chen Hao H

Aging 20210110 3

In this study, we investigated the role of tumor-associated macrophages (TAMs) in the progression of pancreatic ductal adenocarcinoma (PDAC). PDAC patients with higher levels of CD68<sup>+</sup> TAMs exhibited shorter overall survival. In Transwell assays, PDAC cells incubated with TAMs or conditioned media from TAM cells (TAM-CM) showed higher migration and invasion rates than controls. PET/CT scan analysis of orthotopic PDAC model mice revealed greater primary tumor growth and liver metastasis ...[more]

PMID: 33428605

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive carcinoma entities worldwide with early and rapid dissemination. Recently, we discussed the role of microRNAs as epigenetic regulators of Epithelial-to-Mesenchymal Transition (EMT) in PDAC. In this study, we investigated their value as diagnostic and prognostic markers in tissue and blood samples of 185 patients including PDAC, non-malignant pancreatic disorders, and age-matched healthy controls. Expression of the microRNA-200-family (microRNAs -141, -200a, -200b, -200c, -429) and microRNA-148a was significantly downregulated in tissue of PDAC Union internationale contre le cancer (UICC) Stage II. Correspondingly, stromal PDAC tissue showed strong expression of Fibronectin, Vimentin, and ZEB-1 (Zinc finger E-box-binding homeobox) versus low expression of E-cadherin. Transient transfection of microRNA-200b and microRNA-200c mimics resulted in the downregulation of their key target ZEB-1. Inversely, blood serum analyses of patients with PDAC UICC Stages II, III, and IV showed a significant over-expression of microRNA-200-family members, microRNA-148a, microRNA-10b, and microRNA-34a. Correspondingly, Enzyme-linked Immunosorbent Assay (ELISA) analyses revealed a significant over-expression of soluble E-cadherin in serum samples of PDAC patients versus healthy controls. The best diagnostic accuracy to distinguish between PDAC and non-PDAC in this patient collective could be achieved in tissue by microRNA-148a with an area under the receiver-operating-characteristic (ROC) curve (AUC) of 0.885 and in blood serum by a panel of microRNA-141, -200b, -200c, and CA.19-9 with an AUC of 0.890. Both diagnostic tools outreach the diagnostic performance of the currently most common diagnostic biomarker CA.19-9 (AUC of 0.834). Kaplan Meier survival analysis of this patient collective revealed an improved overall survival in PDAC patients with high expression of tissue-related microRNA-34a, -141, -200b, -200c, and -429. In conclusion, EMT-regulating microRNAs have great potential as liquid and solid biopsy markers in PDAC patients. Their prognostic and therapeutic benefits remain important tasks for future studies.

Project description:IntroductionDamage specific DNA binding protein 2 (DDB2) is an UV-indiced DNA damage recognition factor and regulator of cancer development and progression. DDB2 has dual roles in several cancers, either as an oncogene or as a tumor suppressor gene, depending on cancer localization. Here, we investigated the unresolved role of DDB2 in pancreatic ductal adenocarcinoma (PDAC).MethodsThe expression level of DDB2 in pancreatic cancer tissues and its correlation with patient survival were evaluated using publicly available data. Two PDAC cell models with CRISPR-modified DDB2 expression were developed: DDB2 was repressed in DDB2-high T3M4 cells (T3M4 DDB2-low) while DDB2 was overexpressed in DDB2-low Capan-2 cells (Capan-2 DDB2-high). Immunofluorescence and qPCR assays were used to investigate epithelial-to-mesenchymal transition (EMT) in these models. Migration and invasion properties of the cells were also determined using wound healing and transwell assays. Sensitivity to 5-fluorouracil (5-FU), oxaliplatin, irinotecan and gemcitabine were finally investigated by crystal violet assays.ResultsDDB2 expression level was reduced in PDAC tissues compared to normal ones and DDB2-low levels were correlated to shorter disease-free survival in PDAC patients. DDB2 overexpression increased expression of E-cadherin epithelial marker, and decreased levels of N-cadherin mesenchymal marker. Conversely, we observed opposite effects in DDB2 repression and enhanced transcription of SNAIL, ZEB1, and TWIST EMT transcription factors (EMT-TFs). Study of migration and invasion revealed that these properties were negatively correlated with DDB2 expression in both cell models. DDB2 overexpression sensitized cells to 5-fluorouracil, oxaliplatin and gemcitabine.ConclusionOur study highlights the potential tumor suppressive effects of DDB2 on PDAC progression. DDB2 could thus represent a promising therapeutic target or biomarker for defining prognosis and predicting chemotherapy response in patients with PDAC.

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Tumor-associated macrophages promote pancreatic ductal adenocarcinoma progression by inducing epithelial-to-mesenchymal transition.

Publications

Tumor-associated macrophages promote pancreatic ductal adenocarcinoma progression by inducing epithelial-to-mesenchymal transition.

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