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NNMT alters Akt phosphorylation and affects the association between the transcription factor SP1 and the MMP2 promoter ( NNMT knockdown in a more aggressive squamous cell line contributed to the downregulation of epithelial–mesenchymal transition (EMT)-related genes, including MMP9 , osteopontin ( OPN ), and versican core protein ( VCAN ), which are involved in focal adhesion and extracellular matrix (ECM)–receptor interaction ( Cancer-associated fibroblasts (CAFs) are a fibroblast subpopulation that secrete pro-oncogenic cytokines and ECM-modifying factors promoting and supporting malignant cell growth and invasion ( via MMPs, ROS, and tumor-derived transforming growth factor-β (TGF-β) ( NNMT mRNA expression is associated positively with CAF markers ( NNMT knockdown can convert CAFs to normal fibroblasts, which suggests bidirectional interconversion ( Cancer Stem Cells Tumor initiation and progression is driven by CSCs that have the ability to self-renew and differentiate into cells to avoid clone depletion ( NNMT reduces GSC growth and self-renewal in vitro and is more effective than nicotinamide phosphoribosyltransferase (NAMPT)