MMP14‐Dependent Activation of TGF‐β Signaling Enhances Malignancies via Promoting Necroptosis in Glioblastoma

Glioblastoma (GBM) exhibits profound genetic heterogeneity and poor prognosis, and a wide range of biological processes are proved to be enrolled in its tumorigenesis and progression. Necroptosis, which is identified as a regulated cell death process, has been widely confirmed to be essential in shaping malignant behaviors among multiple tumors; nevertheless, the functions of necroptosis in GBM still remain elusive. Herein, matrix metalloproteinase-14 (MMP14) was identified as a necroptosis-related hub gene in GBM by using weighted gene co-expression network analysis (WGCNA) of bulk transcriptomic data. Moreover, single-cell analysis and spatial transcriptomics mapped a cell subpopulation in which MMP14 and necroptosis are closely correlated. Additionally, MMP14 emerged as a poor prognostic marker in GBM. Functionally, knockdown of MMP14 suppressed GBM malignant behavior, including proliferation, immigration, invasion, and tumorigenesis, with an increased susceptibility to necroptosis. As an underlying mechanism, TGF-β signaling was critical for MMP14-mediated necroptosis activation, with SMAD Family Member 2 (SMAD2) directly binding to the Receptor-Interacting Protein 1 (RIP1) promoter. Altogether, MMP14 promotes a range of malignant behaviors and orchestrates a TGF-β-dependent necroptosis heterogeneity landscape in GBM; therefore, targeting MMP14-TGF-β signaling could be a novel strategy to counteract therapeutic resistance in GBM.