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Systematic analysis of TREM2 and its carcinogenesis in pancreatic cancer
Wanting Zheng1, Wangjianfei Yu2, Ruheng Hua1
1Department of General Surgery, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China.
Background:
Triggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane immunoglobulin-superfamily receptor, is expressed primarily on cells such as macrophages and dendritic cells. TREM2 has been shown to be associated with diseases such as neurodegeneration, fatty liver, obesity, and atherosclerosis. Currently, it has become one of the hotspots in oncology research. However, the role of TREM2 in pan-cancer, especially pancreatic cancer, remains unclear.
Methods:
We used the Tumor-immune System Interactions Database (TISIDB) to explore TREM2 expression differences, Tumor Immune Single-cell Hub 2 (TISCH2) to explore TREM2 expression distribution, Tumor IMmune Estimation Resource 2.0 (TIMER 2.0) to explore immune infiltration, cBio Cancer Genomics Portal (cBioPortal) to explore genetic variation, Genomics of Drug Sensitivity in Cancer (GDSC) to explore drug resistance, and Kaplan-Meier plotter database to explore the relationship between TREM2 and prognosis in pancreatic cancer. In addition, we used The Cancer Genome Atlas-pancreatic adenocarcinoma (TCGA-PAAD) and normal pancreas samples from the Genotype-Tissue Expression (GTEx) databases to explore the relationship between TREM2 and lymph node metastasis. We verified the protein level of TREM2 in pancreatic cancer by Human Protein Atlas (HPA) and western blotting and detected the colocalization of TREM2 with malignant cell markers by multiplex immunohistochemistry (mIHC). Finally, we identified the tumor-promoting role of TREM2 in pancreatic cancer via in vitro experiments, such as cell cycle assays, colony formation assays, and transwell migration and invasion assays.
Results:
Our results showed that TREM2 was differentially expressed in various tumors according to different molecular and immune subtypes of pan-cancer. It was found that TREM2 was mainly expressed in monocytes/macrophages. In addition, our study showed that TREM2 expression was closely associated with macrophages in the tumor microenvironment (TME) of pan-cancer. TREM2 was shown to be related to anti-inflammatory and immunosuppressive effects in most cancers. Furthermore, we found that amplification was the main somatic mutation of TREM2 in pan-cancer. Further correlational analysis revealed a significant negative association of TREM2 expression with sensitivity to AZD8186, which is a selective inhibitor of PI3K, but not gemcitabine and paclitaxel. Finally, through the knockdown and overexpression of TREM2, our findings verified that TREM2 on cancer cells promoted the progression of PAAD.
Conclusions:
In conclusion, our comprehensive analysis identified that TREM2 expression level was correlated with the TME and the immunosuppressive effects. In particular, our study indicated that TREM2 was involved in the progression of pancreatic cancer.
Insights
Triggering receptor expressed on myeloid cells 2 (TREM2) is linked to tumor progression and immunosuppression in pancreatic cancer. This research highlights TREM2
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Triggering receptor expressed on myeloid cells 2 (TREM2) is a receptor primarily on macrophages and dendritic cells, implicated in diseases like neurodegeneration and atherosclerosis.
- TREM2 is gaining attention in oncology, but its role in pan-cancer, particularly pancreatic cancer, is not well understood.
Purpose of the Study:
- To investigate the role of TREM2 in pan-cancer, with a specific focus on pancreatic cancer.
- To explore the association of TREM2 with the tumor microenvironment (TME), immune infiltration, and drug sensitivity.
Main Methods:
- Utilized databases like TISIDB, TISCH2, TIMER 2.0, cBioPortal, GDSC, and Kaplan-Meier plotter for expression, immune infiltration, and prognosis analysis.
- Analyzed TCGA-PAAD and GTEx data for lymph node metastasis correlation, HPA and western blotting for protein levels, and mIHC for colocalization.
- Conducted in vitro experiments including cell cycle, colony formation, and transwell assays to determine TREM2's functional role.
Main Results:
- TREM2 expression varied across pan-cancer subtypes and was mainly found in monocytes/macrophages, correlating with immunosuppressive effects in the TME.
- Amplification was the predominant somatic mutation for TREM2 in pan-cancer.
- TREM2 expression negatively correlated with sensitivity to PI3K inhibitor AZD8186 and was confirmed to promote pancreatic ductal adenocarcinoma (PAAD) progression.
Conclusions:
- TREM2 expression is linked to the TME and immunosuppression across various cancers.
- TREM2 plays a tumor-promoting role in pancreatic cancer progression.
