A novel program of infiltrative control in astrocytomas: ADAM23 depletion promotes cell invasion by activating γ-Secretase and NOTCH1 signaling pathway

Background: Diffuse infiltration is a life-threatening growth pattern in malignant astrocytomas and a significant cause of therapy resistance. This pattern is determined by the balance between proliferative and invasive genetic programs and is mainly recapitulated by glioma stem cells (GSCs) during astrocytoma progression. Infiltration results in the GSCs spreading deeply into the surrounding brain tissue, fostering tumor recurrence and making complete surgical resection impossible. We need to thoroughly understand the mechanisms underlying diffuse infiltration to develop effective therapies. Results We found that ADAM23 is downregulated in astrocytoma compared with the normal brain. Based on the clinical data and preclinical models, ADAM23 downregulation is associated with a favorable prognosis in lower-grade astrocytoma patients and correlated with the emergence of a pro-invasive tumor phenotype. The expression of ADAM23 in astrocytoma cells is inversely correlated with increased γ-secretase complex activity, consequently contributing to NOTCH1 pathway activation in GSCs and amyloid-β (Aβ) deposition in the mouse brain. Finally, epigenetic inhibition or administration of γ-secretase inhibitors (GSIs) induced a significant inhibitory effect on the invasive programs, specifically in ADAM23low astrocytoma cells. Conclusions Overall, our findings reveal ADAM23 expression levels as a new prognostic biomarker and a predictive factor of GSI efficacy for diffuse infiltration in ADAM23 low-expressing astrocytomas.