Transcriptomic Profiling of Adhesion GPCRs in Pancreatic Adenocarcinoma Identifies ADGRG7 and ADGRF1 as Novel Diagnostic Biomarkers and Therapeutic Targets
TL;DR
A highly distinct aGPCR dysregulation signature characterized by the massive upregulation of ADGRG7 and ADGRF1 is identified within the PAAD microenvironment, highlighting them as promising diagnostic biomarkers and actionable therapeutic targets for overcoming TME-mediated immunosuppression.
Abstract
Background/Aim: Pancreatic adenocarcinoma (PAAD) is characterized by a desmoplastic, profoundly immunosuppressive tumor microenvironment (TME). Adhesion G protein-coupled receptors (aGPCRs) regulate cell-matrix interactions and immune modulation, yet their specific roles in PAAD remain poorly understood. This study aimed to identify novel tumor-specific aGPCRs and define their functional and immunological landscape. Materials and Methods: Transcriptomic profiles from The Cancer Genome Atlas (TCGA)-PAAD (n=178+4) and the Genotype-Tissue Expression (GTEx)-Pancreas (n=165) cohorts were integrated. Following rigorous batch-effect correction via multi-factor generalized linear modeling, we performed differential expression analysis, biological validation, and functional enrichment (KEGG, GSEA). Immune infiltration was quantified using marker-gene signature scoring, and prognostic weight was assessed via age-adjusted Cox proportional hazards regression. Results: We identified a highly distinct aGPCR dysregulation signature characterized by the massive upregulation of ADGRG7 (log2FC=+3.46, padj=1.92×10−5) and ADGRF1 (log2FC=+2.36, padj=4.10×10−5) alongside the depletion of the macrophage marker ADGRE1. Survival analyses revealed an uncoupling of diagnostic specificity from prognostic weight; unlike ADGRG6, neither ADGRG7 nor ADGRF1 acted as standalone prognostic predictors, suggesting they are uniformly essential neoplastic drivers. Within the PAAD “immune desert,” ADGRG7 positively correlated with residual Th1 niches, whereas ADGRF1 exhibited a distinct myeloid-exclusion phenotype. Conclusion: ADGRG7 and ADGRF1 are foundational, highly tumor-specific aGPCRs within the PAAD microenvironment. Their unique immune correlation profiles and uniform expression highlight them as promising diagnostic biomarkers and actionable therapeutic targets for overcoming TME-mediated immunosuppression.