Transglutaminases are oncogenic biomarkers in human cancers and therapeutic targeting of TGM2 blocks chemoresistance and macrophage infiltration in pancreatic cancer.

Abstract

Transglutaminases (TGs) are multifunctional enzymes exhibiting transglutaminase crosslinking, as well asatypical GTPase/ATPase and kinase activities. Here, we usedan integrated comprehensive analysis to assess the genomic, transcriptomic and immunological landscapes of TGs across cancers. Gene expression and immune cell infiltrationpatterns across cancers were obtained from The Cancer Genome Atlas (TCGA) database and Gene Set Enrichment Analysis (GSEA) datasets. Western blotting, immunofluorescence staining, enzyme-linked immunosorbent assays, and orthotopic xenograft models were used to validate our database-derived results. We found that theoverall expression of TGs (designated as the TG score) is significantly upregulated in multiple cancers and related to aworse patient survival. The expression of TG family members can be regulated through multiple mechanisms at the genetic, epigenetic and transcriptional levels. The expression of transcription factors crucial for epithelial-to-mesenchymal transition (EMT) is commonly correlated with the TG score in many cancer types. Importantly, TGM2 expression displays a close connection with chemoresistance to a wide range of chemotherapeutic drugs. We found thatTGM2 expression, F13A1 expression and the overall TG score were positively correlated with the infiltration of immune cells in all cancer types tested. Functional and clinical verification revealed that ahigher TGM2 expression is linked with aworse patient survival, an increased IC50 value of gemcitabine, and a higher abundance of tumor-infiltrating macrophages in pancreatic cancer. Mechanistically, we found thatincreased C-C motif chemokine ligand 2 (CCL2) release mediated by TGM2 contributes to macrophage infiltration into the tumor microenvironment. Our results reveal the relevance and molecular networks of TG genes in human cancers and highlight the importance of TGM2 in pancreatic cancer, which may provide promising directions for immunotherapy and foraddressing chemoresistance.