Research Project: Bioengineered Matrices Mimicking the Lung Tumor Microenvironment
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Contributors
Funders
ID
EC.00153
Authors
Öztürk, Ece
Faculty Member
Publications
Extracellular matrix sulfation in the tumor microenvironment stimulates cancer stemness and invasiveness
(Wiley, 2024) Bulutay, Pınar; Dansık, Aslı; Dilege, Şükrü; Doğanalp, Efe Can; Erus, Suat; Fırat, Pınar Arıkan; Karaoğlu, İsmail Can; Kızılel, Seda; Kuşoğlu, Alican; Örnek, Deniz; Özdinç, Şevval; Özkan, Sena Nur; Öztürk, Ece; Sarıca, Sevgi; Solaroğlu, İhsan; Solcan, Nuriye; Tanju, Serhan; Tunçbağ, Nurcan; Uzun, Ceren; Yangın, Kardelen; Turan, Duygu; Arlov, Oystein; Cunningham, Katherine; Vunjak-Novakovic, Gordana; Department of Chemical and Biological Engineering; Graduate School of Health Sciences; Graduate School of Sciences and Engineering; KUTTAM (Koç University Research Center for Translational Medicine); School of Medicine; Yes; College of Engineering; GRADUATE SCHOOL OF HEALTH SCIENCES; GRADUATE SCHOOL OF SCIENCES AND ENGINEERING; Research Center; SCHOOL OF MEDICINE
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.
Different decellularization methods in bovine lung tissue reveals distinct biochemical composition, stiffness, and viscoelasticity in reconstituted hydrogels
(American Chemical Society (ACS), 2023) Bulutay, Pınar; Fırat, Pınar Arıkan; Karaoğlu, İsmail Can; Kızılel, Seda; Kuşoğlu, Alican; Örnek, Deniz; Özkan, Sena Nur; Sarıca, Sevgi; Solcan, Nuriye; Yangın, Kardelen; Department of Chemical and Biological Engineering; Graduate School of Health Sciences; Graduate School of Sciences and Engineering; KUTTAM (Koç University Research Center for Translational Medicine); School of Medicine; Yes; College of Engineering; GRADUATE SCHOOL OF HEALTH SCIENCES; GRADUATE SCHOOL OF SCIENCES AND ENGINEERING; Research Center; SCHOOL OF MEDICINE
Extracellula r matri x (ECM)-derived hydrogels are in demand for use in lung tissue engineering to mimic the native microenvironment of cells in vitro. Decellularization of native tissues has been pursued for preser v i n g organotypic ECM while eliminating cellular content and reconstitution into scaffolds which allows re-cellularization for modeling homeostasis, regeneration, or diseases. Achieving mechanical stabi l i t y and understanding the effects of the decellularization process on mechanical parameters of the reconstituted ECM hydrogels present a challenge in the field. Stiffness and viscoelasticity are important characteristics of tissue mechanics that regulate crucial cellular processes and their in vitro representation in engineered models is a current aspiration. The effect of decellulariza-tion on viscoelastic properties of resulting ECM hydrogels has not yet been addressed. The aim of this study was to establish bovine lung tissue decellularization for the first time via pursuing four different protocols and characterization of reconstituted decellularized lung ECM hydrogels for biochemical and mechanical properties. Our data reveal that bovine lungs provide a reproducible alternative to human lungs for disease modeling with optimal retention of ECM components upon decellularization. We demonstrate that the decellularization method significa n t l y affects ECM content, stiffness, and viscoelastic properties of resulting hydrogels. Lastly, we examined the impact of these aspects on viabi l i t y , morphology, and growth of lung cancer cells, healthy bronchial epithelial cells, and patient-derived lung organoids.
