Loss of Fibronectin Fiber Tension in Glioblastoma is Associated with Microvascular Proliferations and Immune Cell Infiltration

Abstract Glioblastoma, the most malignant primary glial brain tumor, is challenging to cure. Its progression involves profound changes in the tumor microenvironment that includes extensive remodeling of the extracellular matrix (ECM). However, the impact of ECM fiber tension on cell‐ECM crosstalk during brain tumor progression has not been explored. To address this, a thoroughly validated peptide tension probe (FnBPA5) is used to stain tissue cryosections and assess fibronectin fiber tension. It is found that in the infiltration zone, microvascular proliferations (MVPs) are filled with low‐tension fibronectin fibers alongside layered endothelial cells and alpha‐smooth muscle actin (α−SMA) expressing cells, in contrast to microvessels (MVs). Also brain tissue areas infiltrated by immune cells—specifically, CD45+/CD68+ macrophages—contained abundant untensed fibronectin fibers. Occasionally, leukocytes formed non‐encapsulated CD45+ aggregates that partially co‐localized with lymphatic‐endothelial‐like cells (LEC‐like). Significantly, the number of leukocytes is directly proportional to the density of collagen I/III fibers. These CD45+ aggregates have morphological similarities with Tertiary Lymphoid Structures (TLS). The discovery that fibronectin fibers lose their tension in MVPs and in immune cell‐infiltrated parenchyma is significant as ECM fiber tension is known to mechano‐tune molecular interactions. The findings introduce the potential for novel therapeutic strategies that exploit ECM mechanics to improve glioblastoma treatment outcomes.