NNMT-LOX-FAK axis orchestrates the intergrowth of fibroblasts and tumor cells in oral squamous cell carcinoma: evidence from the patient-derived assembled organoids

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Abstract
Nicotinamide N-methyltransferase (NNMT) has been reported to link with the methylation reprogramming in cancer cells. However, the role of NNMT in tumor microenvironment (TME) remained elusive. Here, we found that the expression of NNMT was elevated in the stroma of oral squamous cell carcinoma (OSCC). Using a fibroblast-attached organoids (FAOs) model, we found that the stromal NNMT expression contributed to the generation of assembled tumor organoids. In tumor regeneration assay with co-implanted OSCC cells and cancer-associated fibroblasts (CAFs), the tumor-initiating activity was reduced when NNMT in CAFs was silenced. On the contrary, overexpression of NNMT in paracancerous fibroblasts (PFs) accelerated the tumor growth in co-inoculation experiments. Of note, the fibroblast-specific NNMT can regulate the type I collagen deposition in both FAOs and xenograft. Further investigations confirmed that the stromal NNMT-aggravated oncogenic properties were attenuated by treatment with inhibitors targeting either the type I collagen synthesis (e.g. losartan, tranilast, halofuginone), or the focal adhesion kinase (FAK) signal (i.e. defactinib). Mechanistically, overexpression of NNMT reduced the enrichment of H3K27me3 at the promoter of gene encoding lysyl oxidase (LOX), a key enzyme that regulates cross-link formation of type I collagen. Overall, we propose that NNMT-LOX-FAK axis is essential for the intergrowth of cancer cells and fibroblasts during OSCC development, and the NNMT-centric extracellular matrix remodeling is supposed to be a novel therapeutic target for patients with OSCC.