SRGN-Triggered Aggressive and Immunosuppressive Phenotype in a Subset of TTF-1–Negative Lung Adenocarcinomas
Menée à l'aide de lignées cellulaires d'adénocarcinome pulmonaire n'exprimant pas TTF-1 et menée à l'aide d'un modèle murin, cette étude met en évidence le rôle de la serglycine dans les interactions entre les cellules tumorales et le stroma, l'acquisition d'un phénotype agressif et l'immunosuppression
Background : About 20% of lung adenocarcinoma (LUAD) is negative for the lineage-specific oncogene Thyroid transcription factor 1 (TTF-1) and exhibits worse clinical outcome with a low frequency of actionable genomic alterations. To identify molecular features associated with TTF-1–negative LUAD, we compared the transcriptomic and proteomic profiles of LUAD cell lines. SRGN, a chondroitin sulfate proteoglycan Serglycin, was identified as a markedly overexpressed gene in TTF-1–negative LUAD. We therefore investigated the roles and regulation of SRGN in TTF-1–negative LUAD. Methods : Proteomic and metabolomic analyses of 41 LUAD cell lines were done using mass spectrometry. The function of SRGN was investigated in 3 TTF-1–negative and 4 TTF-1–positive LUAD cell lines and in a syngeneic mouse model (n = 5 to 8 mice per group). Expression of SRGN in was evaluated in 94 and 105 surgically resected LUAD tumor specimens using immunohistochemistry. All statistical tests were two-sided. Results : SRGN was markedly overexpressed at mRNA and protein levels in TTF-1–negative LUAD cell lines (P < .001 for both mRNA and protein levels). Expression of SRGN in LUAD tumor tissue was associated with poor outcome (hazard ratio = 4.22, 95% confidential interval = 1.12 to 15.86; likelihood ratio test, P = .03), and with higher expression of Programmed cell death 1 ligand 1 (PD-L1) in tumor cells and higher infiltration of Programmed cell death protein 1 (PD-1)–positive lymphocytes. SRGN regulated expression of PD-L1, as well as proinflammatory cytokines including Interleukin-6 (IL-6), Interleukin-8 (IL-8), and C-X-C motif chemokine 1 (CXCL1) in LUAD cell lines, and increased migratory and invasive properties of LUAD cells and fibroblasts, and enhanced angiogenesis. SRGN was induced by DNA de-methylation resulting from Nicotinamide N-methyltransferase (NNMT)-mediated impairment of methionine metabolism. Conclusion : Our findings suggest that SRGN plays a pivotal role in tumor-stromal interaction and reprogramming into an aggressive and immunosuppressive tumor microenvironment in TTF-1–negative LUAD.