SRGN-Triggered Aggressive and Immunosuppressive Phenotype in a Subset of TTF-1–Negative Lung Adenocarcinomas
Ichidai Tanaka, Delphine Daydé, Mei-Chee Tai, Haruki Mori, Luisa M. Solis, S. C. Tripathi, Johannes F. Fahrmann, Neşe Ünver, Gargy Parhy, Rekha Jain, Edwin R. Parra, Yoshiko Murakami, Clemente Aguilar-Bonavides, Barbara Mino, Müge Çeliktaş, Dilsher Dhillon, Julian P Casabar, Masahiro Nakatochi, Francesco C. Stingo, Veera Baladandayuthapani, Hong Wang, Hiroyuki Katayama, Jennifer B. Dennison, Philip L. Lorenzi, Kim‐Anh Do, Junya Fujimoto, Carmen Behrens, Edwin J. Ostrin, Jaime Rodriguez‐Canales, Tetsunari Hase, Takayuki Fukui, Taisuke Kajino, Seiichi Kato, Yasushi Yatabe, Waki Hosoda, Koji Kawaguchi, Kohei Yokoi, Toyofumi F. Chen‐Yoshikawa, Yoshinori Hasegawa, Adi F. Gazdar, Ignacio I. Wistuba, Samir Hanash, Ayumu Taguchi
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.