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.