LATS1/2 suppress NFκB and aberrant EMT initiation to permit pancreatic progenitor differentiation

Abstract

The Hippo pathway directs cell differentiation during organogenesis, in part by restricting proliferation. How Hippo signaling maintains a proliferation-differentiation balance in developing tissues via distinct molecular targets is only beginning to be understood. Our study makes the unexpected finding that Hippo suppresses nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling in pancreatic progenitors to permit cell differentiation and epithelial morphogenesis. We find that pancreas-specific deletion of the large tumor suppressor kinases 1 and 2 ( Lats1/2 PanKO ) from mouse progenitor epithelia results in failure to differentiate key pancreatic lineages: acinar, ductal, and endocrine. We carried out an unbiased transcriptome analysis to query differentiation defects in Lats1/2 PanKO . This analysis revealed increased expression of NFκB activators, including the pantetheinase vanin1 ( Vnn1 ). Using in vivo and ex vivo studies, we show that VNN1 activates a detrimental cascade of processes in Lats1/2 PanKO epithelium, including (1) NFκB activation and (2) aberrant initiation of epithelial-mesenchymal transition (EMT), which together disrupt normal differentiation. We show that exogenous stimulation of VNN1 or NFκB can trigger this cascade in wild-type (WT) pancreatic progenitors. These findings reveal an unexpected requirement for active suppression of NFκB by LATS1/2 during pancreas development, which restrains a cell-autonomous deleterious transcriptional program and thereby allows epithelial differentiation.

Girdin interaction with vimentin induces EMT and promotes the growth and metastasis of pancreatic ductal adenocarcinoma

“…Epithelial cells undergo various biochemical changes, including the loss of epithelial characteristics and the acquisition of mesenchymal properties (11)(12). The characteristic changes in EMT are the loss of epithelial marker E-cadherin and the increase in mesenchymal markers vimentin and N-cadherin (34,36). Recently, it was revealed that downregulation of Girdin suppressed breast cancer and neuroglioma migration and invasion in vitro and that Girdin may interact with the epithelial marker E-cadherin to regulate cell-cell adhesion (24,26,37).…”

Transgelins: Cytoskeletal Associated Proteins Implicated in the Metastasis of Colorectal Cancer

“…Tumor necrosis factor (TNF) binds to related receptors, predominantly activating I-κB kinase to allow the translocation of NF-κB into the cell nucleus and induce target gene expression (Yang et al, 2020). Braitsch et al (2019) confirmed that the deletion of large tumor suppressor kinases 1 and 2 (LATS1/2) led to NF-κB activation and EMT, which was accompanied by upregulated T-1 expression and ultimately promoted cell migration and invasion. Insulin-like growth factor binding protein-related protein-1 (IGFBP-rP1) was found to be up-regulated in CRC patients with lymph node metastasis CRC patients, who also exhibit up-regulated levels of T-1 (Ruan et al, 2010).…”

Glycyrrhizin Attenuates Carcinogenesis by Inhibiting the Inflammatory Response in a Murine Model of Colorectal Cancer

“…We have previously reported that increased DNA damage due to inflammation may result in the mutation of stem cells, leading to tumor development [ 54 ]. It has been reported that NF-κB is activated by YAP1 [ 55 , 56 ]. To determine whether CSCs involved in inflammation can also cause tumor development, we examined the expression of stem cell markers YAP1 and SOX9, and found that their expression in the cancer cells in the CC group was significantly higher than that in the normal cells of the control group.…”