HepaCAM Suppresses Glioblastoma Stem Cell Invasion in the Brain

Abstract

Glioblastoma (GBM) is a malignant brain cancer that contains sub-populations of highly invasive tumor cells that drive progression and recurrence after surgery and radiochemotherapy. The exact mechanisms that enable GBM cells to disperse from the main tumor mass and navigate throughout the brain microenvironment remain largely unknown. As a result, there is a lack of effective strategies to block cancer cell invasive growth in primary and recurrent GBM. Here we report that hepatocyte cell adhesion molecule (hepaCAM), which is normally expressed in perivascular astrocytes, plays central roles in controlling the invasive growth features of GBM cells. Genetically targeting HEPACAM induces a transition from GBM cell proliferation/self-renewal to invasion. Increased invasion is due, in part, to an activation of focal adhesion signaling pathways and enhanced GBM cell adhesion to the extracellular matrix (ECM) in the brain microenvironment. Transcriptional profiling of GBM cells reveals various HEPACAM-regulated genes with links to polarity and invasion. Collectively, these data show that hepaCAM balances ECM adhesion and signaling pathways to control cancer cell proliferation versus invasion in the brain parenchyma. Targeting select components of the hepaCAM pathway may be an effective way to block tumor progression and recurrence in patients with GBM.

Unravelling glioblastoma heterogeneity by single-cell RNA sequencing

“…Astrocyte markers S100B, SOX9, HEPACAM, and GFAP are highly expressed in clusters 3 and 4, the astrocytes population, along with the CD44, PDGFRA, and EGFR genes. The HEPACAM gene is normally expressed in astrocytes in the human brain and serves the function of reducing glioblastoma cell proliferation and inhibiting invasion in the brain microenvironment by regulating ion homeostasis [3]. SOX9 is an astrocyte-specific marker and is also expressed by neural progenitor cells.…”