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

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.
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Category

Academic article

Language

English

Author(s)

  • 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

Affiliation

  • SINTEF Industry / Biotechnology and Nanomedicine
  • Koç University
  • Columbia University in the City of New York

Year

2024

Published in

Advanced Science

Volume

11

Issue

36

View this publication at Norwegian Research Information Repository