TUBITAK Destekli Projelerden Çıkan Yayınlar Topluluğu
Published January 1, 2024 | Version v1
Journal article Open

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

Creators

  • 1. Koc Univ, Grad Sch Sci & Engn, TR-34450 Istanbul, Turkiye
  • 2. SINTEF Ind, Dept Biotechnol & Nanomed, N-7034 Trondheim, Norway
  • 3. Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA
  • 4. Koc Univ, Chem & Biol Engn, TR-34450 Istanbul, Turkiye
  • 5. Koc Univ, Sch Med, Dept Pathol, TR-34450 Istanbul, Turkiye
  • 6. Koc Univ, Sch Med, Dept Thorac Surg, TR-34450 Istanbul, Turkiye

Description

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.

Files

bib-0c3fe4b1-ccfb-426d-ba02-3ad4165c082f.txt

Files (396 Bytes)

Name Size Download all
md5:6b376287f9161283ac5870dd9bfc7821
396 Bytes Preview Download