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 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, we demonstrate that PGs are heavily expressed in lung adenocarcinoma patients in correlation with invasive phenotype and poor prognosis. We developed a bioengineered human lung tumor model which recapitulates the increase of sGAGs in tumors in an organotypic matrix with independent control of stiffness, viscoelasticity, ligand density and porosity. Our model reveals that increased sulfation stimulates extensive proliferation, epithelial-mesenchymal transition and stemness in cancer cells. We identified the FAK-PI3K-mTOR signaling axis as a mediator of sulfation-induced molecular changes in cells upon activation of a distinct set of RTKs within tumor-mimetic hydrogels. We demonstrate that the transcriptomic landscape of tumor cells in response to increased sulfation resembles native PG-rich patient tumors through employing integrative omics and network modeling approaches.

Impact of various detergent-based immersion and perfusion decellularization strategies on the novel caprine pancreas derived extracellular matrix scaffold

“…This method leads to constructing a 3D scaffold biomaterial integrated with cells and/or factors, which ultimately becomes a promising tool for restoring or replacing the function of a damaged organ or tissue (Liu et al, 2007). Recently, ECM derived from decellularized tissue has been adopted as a promising strategy to enable 3D tissue formation in a variety of porcine organs such as cartilage (Shen et al, 2020), urethra (Simões et al, 2017), lumbar spine (Wu et al, 2017), heart (Zhou et al, 2010), liver and kidney (Wang et al, 2015), and a few bovine organs like ovaries (Nikniaz et al, 2021), spine (Yu et al, 2020), trabecular bone (Shridhar et al, 2019), liver (Ergun et al, 2022) and lungs (Kuşoğlu et al, 2023). These decellularized tissues have successfully retained the ultrastructure as well as organ-specific microenvironmental elements, such as natural ECM proteins and growth factors, which are responsible for cell adhesion and proliferation.…”