Extracellular Matrix Sulfation in the Tumor Microenvironment Stimulates Cancer Stemness and Invasiveness

• Published in: Advanced science 2024-09, Vol.11 (36), p.e2309966-n/a
• Main Authors: Kuşoğlu, Alican, Örnek, Deniz, Dansık, Aslı, Uzun, Ceren, Nur Özkan, Sena, Sarıca, Sevgi, Yangın, Kardelen, Özdinç, Şevval, Sorhun, Duygu Turan, Solcan, Nuriye, Doğanalp, Efe Can, Arlov, Øystein, Cunningham, Katherine, Karaoğlu, Ismail C, Kizilel, Seda, Solaroğlu, Ihsan, Bulutay, Pınar, Fırat, Pınar, Erus, Suat, Tanju, Serhan, Dilege, Şükrü, Vunjak-Novakovic, Gordana, Tuncbag, Nurcan, Öztürk, Ece
• Format: Article
• Language: English
• Subjects: Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - metabolism; Adenocarcinoma of Lung - pathology; cancer; Cell Line, Tumor; Epithelial-Mesenchymal Transition - genetics; Extracellular matrix; extracellular matrix (ECM); Extracellular Matrix - metabolism; Humans; Hydrogels; Kinases; Ligands; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medical prognosis; Molecular weight; Neoplasm Invasiveness; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Patients; Polyethylene glycol; Proteoglycans - genetics; Proteoglycans - metabolism; Signal Transduction; Tissue engineering; tumor microenvironment (TME); Tumor Microenvironment - genetics; tumor models; Tumors; Viscoelasticity
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202309966

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.