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

Abstract

Backgroud:Transglutaminases (TGs) are multifunctional enzymes with transglutaminase cross-linking, atypical GTPase/ATPase and kinase activity. Here, an integrated comprehensive analysis shows the genomic, transcriptomic and immunological landscapes of the TGs varies among different cancers. MethodsGene expression pattern and immune cell in ltration in pan-cancer were obtained from The Cancer Genome Atlas (TCGA) databases and Gene Set Enrichment Analysis (GSEA) datasets. Western blotting, immuno uorescence, ELISA, and orthotopic xenograft model were performed to validate our databasederived results. ResultsThe overall expression of TGs (designated as TG score) is signi cantly upregulated in multiple cancers and related to worse patient survial. The expression of the TG family can be regulated by multiple mechanisms at the genetic, epigenetic and transcriptional levels. Transcriptionfactors crucial for epithelial to mesenchymal transition (EMT) are commonly correlated with TG score in many cancer types.Importantly, TGM2 expression displays a close connection with the chemoresistances of a wide range of chemodrugs. TGM2, F13A1 and overall TG score are positively correlated with the in ltration of immune cells in all cancer types tested. Functional and clinical veri cation reveals that higher TGM2 expression is linked with worse patient survival, increased IC 50 value of gemcitabine, and abundant tumor-in ltrating macrophages in pancreatic cancer. Mechanistically, increased C-C motif chemokine ligand 2 (CCL2) release affored by TGM2 contributes to macrophage in ltration with tumor microenvironment. ConclusionsThese results reveal the relevances and molecular networks of TG genes in human cancers, highlighting the signi cance of TGM2 in pancreatic cancer which may provide some promising directions for immunotherapy and dealing with chemoresistance.

The Role of Transglutaminase 2 in Cancer: An Update

“…Indeed, recent works proposed a role for TG2 in the pathogenesis of pancreatic cancer [109], contributing to chemotherapy resistance [110] and influencing immune infiltration [111]. More specifically, a comprehensive study conducted to understand the importance of transglutaminases in human cancers revealed that high TG2 levels in pancreatic cancer are associated with worse patient survival, resistance to gemcitabine, and an increase in macrophage recruitment due to the release of the chemokine CCL2 by cancer cells [111]; see Figure 8. Additionally, two recent works highlighted how TG2 can stimulate cancer growth through the activation of YAP/TAZ transcription factors.…”

Targeting circulating tumor cells to prevent metastases

“…TGM2 is a multifunctional enzyme that promotes cell adhesion, migration, and extracellular matrix remodeling [ 40 ]. CD44 and TGM2 are present in every CTCs and gained attention as novel detection markers [ 41 , 43 ] and potential therapeutic targets [ 40 ]–[ 42 , 44 ].…”

“…While the links between CD44, TGM2, and metastasis have already been established, further research is needed to advance our understanding of the role of CD44 and TGM2 in EMT and MET [ 41 , 43 , 45 ]. It is also essential to evaluate their potential as detection markers and consider their implementation in CTCs-targeting therapies to prevent metastasis.…”

A pan-cancer analysis of the oncogenic and immunological roles of transglutaminase 1 (TGM1) in human cancer

“…With the increase in population aging, the burden of disease on health is expected to become increasingly heavy (Zhang et al 2023 ). Statistics indicate that the likelihood of cancer in individuals aged 65 and above is ten times higher compared to those under 65, and the aging process is closely linked to tumorigenesis (Wang et al 2022 ).…”

“…The conformation of TGM2 is regulated by cellular stimuli, such as changes in calcium levels, resulting in different biological effects (Lai and Greenberg 2013 ). Several studies have shown that TGM2 exhibits strong expression and activity in the stromal tissue surrounding tumors, indicating its involvement in tumor aggressiveness (Malkomes et al 2023 ; Zhang et al 2023 ). Due to its diverse functions and implications in disease, TGM2 has emerged as a potential therapeutic target.…”