Increased Gremlin1 Expression in Pancreatic Ductal Adenocarcinoma Promotes a Fibrogenic Stromal Microenvironment.

IF 1.7 4区医学 Q3 GASTROENTEROLOGY & HEPATOLOGY

Pancreas Pub Date : 2024-11-01 Epub Date: 2024-06-04 DOI:10.1097/MPA.0000000000002378

Rachel R Tindall, Erika Y Faraoni, Jiajing Li, Yinjie Zhang, Shun-Ming Ting, Beanna Okeugo, Xiurong Zhao, Yuying Liu, Mamoun Younes, Qiang Shen, Jennifer M Bailey-Lundberg, Yanna Cao, Tien C Ko

{"title":"Increased Gremlin1 Expression in Pancreatic Ductal Adenocarcinoma Promotes a Fibrogenic Stromal Microenvironment.","authors":"Rachel R Tindall, Erika Y Faraoni, Jiajing Li, Yinjie Zhang, Shun-Ming Ting, Beanna Okeugo, Xiurong Zhao, Yuying Liu, Mamoun Younes, Qiang Shen, Jennifer M Bailey-Lundberg, Yanna Cao, Tien C Ko","doi":"10.1097/MPA.0000000000002378","DOIUrl":null,"url":null,"abstract":"Objective: Pancreatic ductal adenocarcinoma (PDAC) microenvironment is primarily composed of cancer-associated fibroblasts and immune cells. Gremlin1 (Grem1) is a profibrogenic factor that promotes tumorigenesis in several cancers. However, the role of Grem1 in the PDAC microenvironment is not defined.Materials and methods: We correlated Grem1 levels with activated stroma and immune cells in human PDAC using The Cancer Genome Atlas RNA-sequencing data and characterized expression of Grem1 transcripts and isoforms in pancreatic cell lines and PDAC tissues. We assessed the role of Grem1 in the microenvironment by in vitro studies.Results: Grem1 expression is associated with an activated stroma and increased M1 and M2 macrophages. Only full length Grem1 variant 1 and isoform 1 were detectable in human pancreatic cells, and remarkably high levels of Grem1 were observed in pancreatic fibroblasts. Immunohistochemistry detected Grem1 protein in PDAC tumor and stromal cells, which correlated with infiltrating macrophages in PDAC tumors. Grem1 knockdown in cancer-associated fibroblasts suppressed transforming growth factor β-induced extracellular matrix proteins. Grem1 recombinant protein treatment in vitro increased M1 and M2 macrophages.Conclusions: Grem1 acts as a profibrogenic factor in the PDAC microenvironment via modulation of fibroblasts and macrophages. Grem1 may have the potential to be developed as a therapeutic target for PDAC.","PeriodicalId":19733,"journal":{"name":"Pancreas","volume":" ","pages":"e808-e817"},"PeriodicalIF":1.7000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11615151/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pancreas","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/MPA.0000000000002378","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/4 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Objective: Pancreatic ductal adenocarcinoma (PDAC) microenvironment is primarily composed of cancer-associated fibroblasts and immune cells. Gremlin1 (Grem1) is a profibrogenic factor that promotes tumorigenesis in several cancers. However, the role of Grem1 in the PDAC microenvironment is not defined.

Materials and methods: We correlated Grem1 levels with activated stroma and immune cells in human PDAC using The Cancer Genome Atlas RNA-sequencing data and characterized expression of Grem1 transcripts and isoforms in pancreatic cell lines and PDAC tissues. We assessed the role of Grem1 in the microenvironment by in vitro studies.

Results: Grem1 expression is associated with an activated stroma and increased M1 and M2 macrophages. Only full length Grem1 variant 1 and isoform 1 were detectable in human pancreatic cells, and remarkably high levels of Grem1 were observed in pancreatic fibroblasts. Immunohistochemistry detected Grem1 protein in PDAC tumor and stromal cells, which correlated with infiltrating macrophages in PDAC tumors. Grem1 knockdown in cancer-associated fibroblasts suppressed transforming growth factor β-induced extracellular matrix proteins. Grem1 recombinant protein treatment in vitro increased M1 and M2 macrophages.

Conclusions: Grem1 acts as a profibrogenic factor in the PDAC microenvironment via modulation of fibroblasts and macrophages. Grem1 may have the potential to be developed as a therapeutic target for PDAC.

查看原文本刊更多论文

胰腺导管腺癌中 Gremlin1 表达的增加促进了纤维基质微环境的形成。

目的：胰腺导管腺癌（PDAC）的微环境主要由癌症相关成纤维细胞（CAF）和免疫细胞组成。Gremlin1（Grem1）是一种促癌因子，可促进多种癌症的肿瘤发生。然而，Grem1在PDAC微环境中的作用尚未得到充分定义：我们利用癌症基因组图谱（The Cancer Genome Atlas，TCGA）的RNA测序数据将Grem1水平与人PDAC中活化的基质和免疫细胞相关联，并描述了Grem1转录物和同工酶在胰腺细胞系和PDAC组织中的表达特征。我们通过体外研究评估了Grem1在微环境中的作用：结果：Grem1的表达与活化的基质以及M1和M2巨噬细胞的增加有关。在人胰腺细胞中只能检测到全长 Grem1 变体 1 和同工酶 1，而在胰腺成纤维细胞中能观察到显著高水平的 Grem1（P < 0.05）。免疫组化在 PDAC 肿瘤细胞和基质细胞中检测到 Grem1 蛋白，这与 PDAC 肿瘤中浸润的巨噬细胞有关。CAFs中的Grem1基因敲除抑制了转化生长因子（TGF）-β诱导的细胞外基质蛋白（P < 0.05）。体外处理 Grem1 重组蛋白可增加 M1 和 M2 巨噬细胞（P < 0.05）：结论：Grem1通过调节成纤维细胞和巨噬细胞在PDAC微环境中充当嗜碱性因子。Grem1有可能成为PDAC的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Pancreas 医学-胃肠肝病学

CiteScore

4.70

自引率

3.40%

发文量

289

审稿时长

1 months

期刊介绍： Pancreas provides a central forum for communication of original works involving both basic and clinical research on the exocrine and endocrine pancreas and their interrelationships and consequences in disease states. This multidisciplinary, international journal covers the whole spectrum of basic sciences, etiology, prevention, pathophysiology, diagnosis, and surgical and medical management of pancreatic diseases, including cancer.