Alican Kuşoğlu, Deniz Örnek, Aslı Dansık, Ceren Uzun, Sena Nur Özkan, Sevgi Sarıca, Kardelen Yangın, Şevval Özdinç, Duygu Turan Sorhun, Nuriye Solcan, Efe Can Doğanalp, Øystein Arlov, Katherine Cunningham, Ismail C Karaoğlu, Seda Kizilel, Ihsan Solaroğlu, Pınar Bulutay, Pınar Fırat, Suat Erus, Serhan Tanju, Şükrü Dilege, Gordana Vunjak-Novakovic, Nurcan Tuncbag, Ece Öztürk
{"title":"Extracellular Matrix Sulfation in the Tumor Microenvironment Stimulates Cancer Stemness and Invasiveness.","authors":"Alican Kuşoğlu, Deniz Örnek, Aslı Dansık, Ceren Uzun, Sena Nur Özkan, Sevgi Sarıca, Kardelen Yangın, Şevval Özdinç, Duygu Turan Sorhun, Nuriye Solcan, Efe Can Doğanalp, Øystein Arlov, Katherine Cunningham, Ismail C Karaoğlu, Seda Kizilel, Ihsan Solaroğlu, Pınar Bulutay, Pınar Fırat, Suat Erus, Serhan Tanju, Şükrü Dilege, Gordana Vunjak-Novakovic, Nurcan Tuncbag, Ece Öztürk","doi":"10.1002/advs.202309966","DOIUrl":null,"url":null,"abstract":"<p><p>Tumor extracellular matrices (ECM) exhibit aberrant changes in composition and mechanics compared to normal tissues. Proteoglycans (PG) are vital regulators of cellular signaling in the ECM with the ability to modulate receptor tyrosine kinase (RTK) activation via their sulfated glycosaminoglycan (sGAG) side chains. However, their role on tumor cell behavior is controversial. Here, it is demonstrated that PGs are heavily expressed in lung adenocarcinoma (LUAD) patients in correlation with invasive phenotype and poor prognosis. A bioengineered human lung tumor model that recapitulates the increase of sGAGs in tumors in an organotypic matrix with independent control of stiffness, viscoelasticity, ligand density, and porosity, is developed. This model reveals that increased sulfation stimulates extensive proliferation, epithelial-mesenchymal transition (EMT), and stemness in cancer cells. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase (PI3K) signaling axis is identified as a mediator of sulfation-induced molecular changes in cells upon activation of a distinct set of RTKs within tumor-mimetic hydrogels. The study shows that the transcriptomic landscape of tumor cells in response to increased sulfation resembles native PG-rich patient tumors by employing integrative omics and network modeling approaches.</p>","PeriodicalId":117,"journal":{"name":"Advanced Science","volume":null,"pages":null},"PeriodicalIF":14.3000,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Advanced Science","FirstCategoryId":"88","ListUrlMain":"https://doi.org/10.1002/advs.202309966","RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Tumor extracellular matrices (ECM) exhibit aberrant changes in composition and mechanics compared to normal tissues. Proteoglycans (PG) are vital regulators of cellular signaling in the ECM with the ability to modulate receptor tyrosine kinase (RTK) activation via their sulfated glycosaminoglycan (sGAG) side chains. However, their role on tumor cell behavior is controversial. Here, it is demonstrated that PGs are heavily expressed in lung adenocarcinoma (LUAD) patients in correlation with invasive phenotype and poor prognosis. A bioengineered human lung tumor model that recapitulates the increase of sGAGs in tumors in an organotypic matrix with independent control of stiffness, viscoelasticity, ligand density, and porosity, is developed. This model reveals that increased sulfation stimulates extensive proliferation, epithelial-mesenchymal transition (EMT), and stemness in cancer cells. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase (PI3K) signaling axis is identified as a mediator of sulfation-induced molecular changes in cells upon activation of a distinct set of RTKs within tumor-mimetic hydrogels. The study shows that the transcriptomic landscape of tumor cells in response to increased sulfation resembles native PG-rich patient tumors by employing integrative omics and network modeling approaches.
期刊介绍:
Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.