Researcher: Doğanalp, Efe Can
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Doğanalp, Efe Can
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Publication Open Access Extracellular matrix sulfation in the tumor microenvironment stimulates cancer stemness and invasiveness(Wiley, 2024) Arlov, Oystein; Cunningham, Katherine; Vunjak-Novakovic, Gordana; Department of Chemical and Biological Engineering; Department of Chemical and Biological Engineering; Kızılel, Seda; Kuşoğlu, Alican; Örnek, Deniz; Dansık, Aslı; Özkan, Sena Nur; Sarıca, Sevgi; Yangın, Kardelen; Özdinç, Şevval; Solcan, Nuriye; Doğanalp, Efe Can; Karaoğlu, İsmail Can; Solaroğlu, İhsan; Bulutay, Pınar; Fırat, Pınar Arıkan; Erus, Suat; Tanju, Serhan; Dilege, Şükrü; Tunçbağ, Nurcan; Öztürk, Ece; Uzun, Ceren; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); College of Engineering; Graduate School of Health Sciences; Graduate School of Sciences and Engineering; School of MedicineTumor 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.