SRGN-Triggered Aggressive and Immunosuppressive Phenotype in a Subset of TTF-1–Negative Lung Adenocarcinomas

• Published in: JNCI : Journal of the National Cancer Institute Vol. 114; no. 2; pp. 290 - 301
• Main Authors: Tanaka, Ichidai, Dayde, Delphine, Tai, Mei Chee, Mori, Haruki, Solis, Luisa M, Tripathi, Satyendra C, Fahrmann, Johannes F, Unver, Nese, Parhy, Gargy, Jain, Rekha, Parra, Edwin R, Murakami, Yoshiko, Aguilar-Bonavides, Clemente, Mino, Barbara, Celiktas, Muge, Dhillon, Dilsher, Casabar, Julian Phillip, Nakatochi, Masahiro, Stingo, Francesco, Baladandayuthapani, Veera, Wang, Hong, Katayama, Hiroyuki, Dennison, Jennifer B, Lorenzi, Philip L, Do, Kim-Anh, Fujimoto, Junya, Behrens, Carmen, Ostrin, Edwin J, Rodriguez-Canales, Jaime, Hase, Tetsunari, Fukui, Takayuki, Kajino, Taisuke, Kato, Seiichi, Yatabe, Yasushi, Hosoda, Waki, Kawaguchi, Koji, Yokoi, Kohei, Chen-Yoshikawa, Toyofumi F, Hasegawa, Yoshinori, Gazdar, Adi F, Wistuba, Ignacio I, Hanash, Samir, Taguchi, Ayumu
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 07.02.2022; Oxford Publishing Limited (England)
• Subjects: Adenocarcinoma; Adenocarcinoma of Lung - genetics; Angiogenesis; Animals; Apoptosis; Cell death; Cell migration; Chemokines; Chondroitin sulfate; Confidence intervals; Cytokines; Demethylation; Deoxyribonucleic acid; DNA; DNA-Binding Proteins; Editor's Choice; Fibroblasts; Gene expression; Humans; Immunohistochemistry; Inflammation; Interleukin 6; Interleukin 8; Invasiveness; Likelihood ratio; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lungs; Lymphocytes; Mass spectrometry; Mass spectroscopy; Metabolism; Metabolomics; Metastases; Methionine; Methyltransferase; Mice; Nicotinamide; PD-L1 protein; Phenotype; Phenotypes; Proteins; Proteoglycans; Proteoglycans - metabolism; Proteomics; Statistical analysis; Statistical tests; Thyroid; Thyroid Nuclear Factor 1 - genetics; Transcription Factors; Tumor cells; Tumor Microenvironment; Tumors; Vesicular Transport Proteins - metabolism
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/djab183

Abstract Background Approximately 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 was evaluated in 94 and 105 surgically resected LUAD tumor specimens using immunohistochemistry. All statistical tests were 2-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% confidence 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–positive lymphocytes. SRGN regulated expression of PD-L1 as well as proinflammatory cytokines, including Interleukin-6, Interleukin-8, and C-X-C motif chemokine 1 in LUAD cell lines; increased migratory and invasive properties of LUAD cells and fibroblasts; and enhanced angiogenesis. SRGN was induced by DNA demethylation resulting from Nicotinamide N-methyltransferase–mediated impairment of methionine metabolism. Conclusions 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.