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SRGN-Triggered Aggressive and Immunosuppressive Phenotype in a Subset of TTF-1-Negative Lung Adenocarcinomas
Ichidai Tanaka1,2, Delphine Dayde1, Mei Chee Tai1
1Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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.
Insights
Serglycin (SRGN) is overexpressed in Thyroid transcription factor 1-negative lung adenocarcinoma (LUAD), promoting aggressive tumor behavior and immune suppression. Targeting SRGN may offer new therapeutic strategies for this LUAD subtype.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Lung adenocarcinoma (LUAD) accounts for approximately 20% of cases that are negative for the Thyroid transcription factor 1 (TTF-1) oncogene.
- TTF-1-negative LUAD exhibits poorer clinical outcomes and fewer actionable genomic alterations.
- Identifying molecular drivers in TTF-1-negative LUAD is crucial for developing targeted therapies.
Purpose of the Study:
- To identify molecular features associated with TTF-1-negative LUAD.
- To investigate the role and regulation of Serglycin (SRGN) in TTF-1-negative LUAD.
Main Methods:
- Comparative transcriptomic and proteomic analyses of LUAD cell lines.
- Functional investigation of SRGN in LUAD cell lines and a syngeneic mouse model.
- Immunohistochemical evaluation of SRGN expression in LUAD tumor specimens.
Main Results:
- SRGN was significantly overexpressed at both mRNA and protein levels in TTF-1-negative LUAD cell lines.
- SRGN expression correlated with poor patient outcome, increased Programmed cell death 1 ligand 1 (PD-L1) expression, and enhanced immune cell infiltration.
- SRGN promoted tumor cell migration, invasion, angiogenesis, and was regulated by DNA demethylation via Nicotinamide N-methyltransferase.
Conclusions:
- SRGN plays a critical role in tumor-stromal interactions within TTF-1-negative LUAD.
- SRGN contributes to an aggressive and immunosuppressive tumor microenvironment.
- SRGN represents a potential therapeutic target for TTF-1-negative LUAD.
