Atypical cadherin FAT1: A central regulator of the common oncogenic pathways in glioblastoma

Abstract

Glioblastoma is the most aggressive tumor arising from astrocytic cells and is resistant to standard therapies due to its extreme tumor heterogeneity, diverse genetic mutations, and supportive tumor microenvironment. Recent investigations from our laboratory and from other researchers have identified the atypical cadherin FAT1 as one of the oncogenic molecules regulating diverse signaling complexes that facilitate tumor progression in glioblastoma. On the basis of our published and ongoing work, the emerging patterns highlight FAT1 as a central regulator of various downstream signaling pathways that promote the oncogenic features of glioblastoma by upregulating inflammation, HIF-1α, and epithelial-to-mesenchymal transition/stemness under severe hypoxia, mediating immune evasion, and regulating autophagy. Glioblastoma patients with high-FAT1-expressing tumors showed poor overall survival. A preclinical study in nude mice using FAT1-knockout U87MG cells showed delayed tumor growth and reduced tumor volume, reflecting FAT1’s role as a tumor promoter. Overall, FAT1 represents a promising target for combination therapy with immunotherapy and autophagy modulators in glioblastoma. This review covers the role of FAT1 in regulating the downstream oncogenic molecules and pathways, current progress in understanding FAT1 function, and its potential use as a marker for patient stratification and FAT1-targeted interventions in glioblastoma.