Kuang-hung Cheng
Assistant Professor at the Institute of Biomedical Sciences at National Sun Yat-sen University in Taiwan
Title: TGIF1 loss contributes to progression of KRASG12D-induced pancreatic ductal adenocarcinoma involving HAS2-CD44 activation and PD-L1 upregulation.
Biography
Biography: Kuang-hung Cheng
Abstract
The identification of the TGIF1 (TG-interacting factor 1) was found to be a nuclear transcriptional corepressor of TGFb1/Smad signaling pathway. TGIF1 has been implicated in the pathogenesis of various types of human cancer, however, the prognostic role of TGIF1 is still controversial, and no role for TGIF1 has yet been indicated in pancreatic ductal adenocarcinoma (PDAC). In this study, we demonstrated that conditional deletion of TGIF1 in the mouse pancreas had no discernible effect on pancreatic development or physiology. Notably, TGIF1 loss cooperated with KrasG12D in the rapid development of PDAC in mice, with a penetrance of 100%. Moreover, we demonstrated that KrasG12D in the context of TGIF1 plus p53 loss induced PDAC with shorter latency and greater propensity for distant metastases, compared with the Pdx-1CreKrasP53L/L model. Deciphering the molecular mechanism highlighted the activation of the hyaluronan synthase 2 (HAS2)-CD44 cancer stemness pathway and upregulation of the immune checkpoint regulator PD-L1 upon TGIF1 loss in PDAC facilitate the epithelial–mesenchymal transition (EMT) and tumor immune suppression, thereby accelerating the development of PDAC metastasis. Notably, TGIF1 silencing also contributed to the alteration of the protein levels of DNMT1, HAT1 and HDAC1 in PDAC, suggesting that TGIF1 might function as an epigenetic regulator and response for aberrant EMT gene expression during PDAC progression. Ultimately, we demonstrate that targeting the HAS2 pathway in TGIF1 loss of PDAC could be a promising therapeutic strategy for improving the clinical efficacy against PDAC metastasis.