Systematic analysis of TREM2 and its carcinogenesis in pancreatic cancer

### Background:
Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor belonging to the immunoglobulin superfamily, primarily expressed on macrophages and dendritic cells. TREM2 has been linked to various diseases, including neurodegeneration, fatty liver, obesity, and atherosclerosis. It has recently emerged as a focal point in oncology research. However, the role of TREM2 in pan-cancer, particularly in pancreatic cancer, remains unclear.

### Methods:
To investigate TREM2, we utilized several databases: the Tumor-immune System Interactions Database (TISIDB) to assess expression differences, Tumor Immune Single-cell Hub 2 (TISCH2) to examine expression distribution, and Tumor IMmune Estimation Resource 2.0 (TIMER 2.0) to analyze immune infiltration. We also explored genetic variation through the cBio Cancer Genomics Portal (cBioPortal), drug resistance via the Genomics of Drug Sensitivity in Cancer (GDSC), and the relationship between TREM2 and pancreatic cancer prognosis using the Kaplan-Meier plotter database. Additionally, we examined the link between TREM2 and lymph node metastasis by analyzing data from The Cancer Genome Atlas-pancreatic adenocarcinoma (TCGA-PAAD) and normal pancreas samples from the Genotype-Tissue Expression (GTEx) databases. Protein levels of TREM2 in pancreatic cancer were verified using the Human Protein Atlas (HPA) and western blotting, while its colocalization with malignant cell markers was detected through multiplex immunohistochemistry (mIHC). Finally, we confirmed the tumor-promoting role of TREM2 in pancreatic cancer through in vitro experiments, including cell cycle assays, colony formation assays, and transwell migration and invasion assays.

### Results:
Our findings revealed that TREM2 is differentially expressed across various tumors depending on molecular and immune subtypes within pan-cancer. TREM2 was predominantly expressed in monocytes/macrophages, and its expression was closely linked to macrophages in the tumor microenvironment (TME) across multiple cancers. TREM2 was associated with anti-inflammatory and immunosuppressive effects in most cancers. Additionally, we identified amplification as the primary somatic mutation of TREM2 in pan-cancer. Correlation analysis demonstrated a significant negative relationship between TREM2 expression and sensitivity to AZD8186, a selective PI3K inhibitor, but not to gemcitabine or paclitaxel. Finally, our experiments with TREM2 knockdown and overexpression confirmed that TREM2 in cancer cells promotes the progression of pancreatic adenocarcinoma (PAAD).

### Conclusions:
In summary, our comprehensive analysis revealed that TREM2 expression is closely associated with the tumor microenvironment and immunosuppressive effects. Notably, our study suggests that TREM2 plays a significant role in the progression of pancreatic cancer.