SRGN-Triggered Aggressive and Immunosuppressive Phenotype in a Subset of TTF-1–Negative Lung Adenocarcinomas. (15th September 2021)

• Record Type: Journal Article
• 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;
• Is Part Of: Journal of the National Cancer Institute. Volume 114:Number 2(2022)
• Page Start: 290
• Page End: 301
• Publication Date: 2021-09-15
• Subjects: Cancer -- Periodicals; Cancer -- Research -- Periodicals; 616.994
• DOI: 10.1093/jnci/djab183
• Languages: English
• ISSNs: 0027-8874

Abstract

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.