Mackenzie K. Callaway , Brock J. Noonan , Kathryn L. Schwertfeger , Paolo P. Provenzano
{"title":"Extracellular matrix architecture promotes immunosuppressive microenvironments in pancreatic cancer","authors":"Mackenzie K. Callaway , Brock J. Noonan , Kathryn L. Schwertfeger , Paolo P. Provenzano","doi":"10.1016/j.matbio.2025.09.004","DOIUrl":null,"url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer with poor clinical outcomes, due in part to altered fibrotic environments and striking immune dysfunction. Physical properties within tumors, such as aligned extracellular matrix (ECM) fiber architectures, are fundamental to cancer progression and outcome. However, the influence of ECM alignment on immune cell localization and function within tumors, particularly PDA, remains largely unexplored. Here, analysis of mouse and human PDA reveal an inextricable link between collagen architecture and the distribution of immunosuppressive macrophages in both early preinvasive disease and invasive carcinomas. <em>In vitro</em> characterization of primary macrophages demonstrates alignment alone is sufficient to induce elongation, polarization, and immunosuppressive activity, including suppression of CD8+ <em>T</em> cell proliferation and motility. Analysis reveals differential focal adhesion kinase (FAK) activity in aligned macrophages, while FAK inhibition (FAKi) disrupts the immunosuppressive phenotype that emerges from encountering ECM alignment. Furthermore, FAKi <em>in vivo</em> significantly reduces the correlation between elongated immunosuppressive macrophages and aligned collagen, further highlighting the opportunity for FAKi to target stromal immunity. Importantly, the correlation between aligned collagen and immunosuppressive macrophages is also observed in human chronic pancreatitis, a known PDA risk factor that has recently been shown to prime stromal ECM alignments for early dissemination, suggesting that precursor disease is also likely to create stromal memory conducive to early immunosuppression. Taken together, these results support a model in which collagen architecture supports early establishment and maintenance of an immunosuppressive microenvironments and defines a role for targeting stromal matrices to “reprogram” patient immunity.</div></div>","PeriodicalId":49851,"journal":{"name":"Matrix Biology","volume":"141 ","pages":"Pages 114-126"},"PeriodicalIF":4.8000,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Matrix Biology","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0945053X25000848","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer with poor clinical outcomes, due in part to altered fibrotic environments and striking immune dysfunction. Physical properties within tumors, such as aligned extracellular matrix (ECM) fiber architectures, are fundamental to cancer progression and outcome. However, the influence of ECM alignment on immune cell localization and function within tumors, particularly PDA, remains largely unexplored. Here, analysis of mouse and human PDA reveal an inextricable link between collagen architecture and the distribution of immunosuppressive macrophages in both early preinvasive disease and invasive carcinomas. In vitro characterization of primary macrophages demonstrates alignment alone is sufficient to induce elongation, polarization, and immunosuppressive activity, including suppression of CD8+ T cell proliferation and motility. Analysis reveals differential focal adhesion kinase (FAK) activity in aligned macrophages, while FAK inhibition (FAKi) disrupts the immunosuppressive phenotype that emerges from encountering ECM alignment. Furthermore, FAKi in vivo significantly reduces the correlation between elongated immunosuppressive macrophages and aligned collagen, further highlighting the opportunity for FAKi to target stromal immunity. Importantly, the correlation between aligned collagen and immunosuppressive macrophages is also observed in human chronic pancreatitis, a known PDA risk factor that has recently been shown to prime stromal ECM alignments for early dissemination, suggesting that precursor disease is also likely to create stromal memory conducive to early immunosuppression. Taken together, these results support a model in which collagen architecture supports early establishment and maintenance of an immunosuppressive microenvironments and defines a role for targeting stromal matrices to “reprogram” patient immunity.
期刊介绍:
Matrix Biology (established in 1980 as Collagen and Related Research) is a cutting-edge journal that is devoted to publishing the latest results in matrix biology research. We welcome articles that reside at the nexus of understanding the cellular and molecular pathophysiology of the extracellular matrix. Matrix Biology focusses on solving elusive questions, opening new avenues of thought and discovery, and challenging longstanding biological paradigms.