Abstract 231P
Background
Mechanisms underlying the early recurrence and metastasis of lung adenocarcinomas (LUAD) remain unclear and deregulating cellular metabolism could be an important process. This study explored the metabolism abnormalities associated with early metastasis of LUAD.
Methods
Untargeted metabolomic and lipidomic analyses were employed to detected metabolism abnormalities. Multiplex immunofluorescence analysis was employed for location of metabolic enzymes. Biological function of core metabolic enzymes was investigated in vitro and in vivo. Published single-cell RNA sequencing database was used for validation.
Results
Untargeted metabolomic and lipidomic analyses were conducted in 21 T1 LUAD with a metastasis within 3 years after curative resection and 19 T1 LUAD without recurrence during the term. Abnormalities in histidine metabolism, arginine and proline metabolism, and nicotinate and nicotinamide metabolism and deregulated lipid metabolism of glycosphingolipid, glycerophospholipid, and sphingolipid were revealed to be associated with early metastasis of LUAD. Nicotinamide N-methyltransferase (NNMT), the core metabolic enzyme of nicotinamide, was validated to be negatively associated with metastasis of LUAD in an individual cohort including 68 patients. Multiplex immunofluorescence analysis of 20 LUAD revealed that NNMT is mainly expressed in cancer-associated fibroblasts (CAF) in tumor microenvironment and downregulation of NNMT in CAF was associated with lymph node metastasis at treatment. Reanalysis of single-cell RNA sequencing data validated the negative association between NNMT and genes associated with oncogenic extracellular matrix in CAF, particularly integrins and collagens. The CAFs were then isolated from LUAD and primarily cultured. Experiments in vitro and in vivo confirmed the negative regulation of NNMT for metastasis-promoting property of CAF in LUAD.
Conclusions
These findings support the NNMT in CAF as a possible metabolic regulator for early metastasis of LUAD. The extracellular matrix remodeling may be involved in the negative regulation. Further investigations are warranted to clarify regulation mechanisms and therapeutic targets.
Legal entity responsible for the study
The authors.
Funding
National Natural Science Foundation of China.
Disclosure
All authors have declared no conflicts of interest.