Ichidai Tanaka1,2, Delphine Dayde1, Mei Chee Tai1, Haruki Mori3, Luisa M Solis1, Satyendra C Tripathi4,5, Johannes F Fahrmann4, Nese Unver4, Gargy Parhy1, Rekha Jain1, Edwin R Parra1, Yoshiko Murakami6, Clemente Aguilar-Bonavides7, Barbara Mino1, Muge Celiktas4, Dilsher Dhillon4, Julian Phillip Casabar4, Masahiro Nakatochi8, Francesco Stingo7,9, Veera Baladandayuthapani7, Hong Wang4,10, Hiroyuki Katayama4, Jennifer B Dennison4, Philip L Lorenzi11, Kim-Anh Do7, Junya Fujimoto1, Carmen Behrens12, Edwin J Ostrin13, Jaime Rodriguez-Canales1, Tetsunari Hase2, Takayuki Fukui14, Taisuke Kajino3, Seiichi Kato6, Yasushi Yatabe6, Waki Hosoda6, Koji Kawaguchi14, Kohei Yokoi14, Toyofumi F Chen-Yoshikawa14, Yoshinori Hasegawa2, Adi F Gazdar15, Ignacio I Wistuba1, Samir Hanash4, Ayumu Taguchi1,3,16. 1. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 2. Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. 3. Division of Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan. 4. Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 5. Department of Biochemistry, All India Institute of Medical Sciences, Nagpur, Maharashtra, India. 6. Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan. 7. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 8. Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan. 9. Department of Statistica, Informatica, Applicazioni "G. Parenti", University of Florence, Florence, Italy. 10. Hangzhou Cosmos Wisdom Mass Spectrometry Center of Zhejiang University Medical School, Xiaoshan District, Hangzhou, Zhejiang, China. 11. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 12. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 13. Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 14. Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan. 15. Hamon Center for Therapeutic Oncology, Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, USA. 16. Division of Advanced Cancer Diagnostics, Department of Cancer Diagnostics and Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
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.
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.
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