Lats1/2 suppress NFkB and aberrant EMT initiation to permit pancreas progenitor differentiation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA522354 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8573710_1.fastq.gz | Fastqsanger.gz | |||
| SRR8573710_2.fastq.gz | Fastqsanger.gz | |||
| SRR8573720_1.fastq.gz | Fastqsanger.gz | |||
| SRR8573720_2.fastq.gz | Fastqsanger.gz | |||
| SRR8573730_1.fastq.gz | Fastqsanger.gz |
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Project description:The Hippo pathway directs cell differentiation during organogenesis, in part by restricting proliferation. How Hippo signaling maintains a proliferation-differentiation balance in developing tissues and its underlying molecular targets are poorly understood. Our study shows that Hippo suppresses NFκB signaling in pancreatic progenitors to permit cell differentiation and developmental progression. We found that pancreas-specific Lats1/2 kinase deletion (Lats1/2PanKO) from mouse progenitor epithelia results in failure to differentiate 3 key pancreatic lineages: acinar, ductal, and endocrine. We performed an unbiased transcriptome analysis to query the differentiation defects in Lats1/2PanKO. This analysis revealed increased NFκB activator expression, including the pantetheinase Vanin1 (Vnn1). Through in vivo and ex vivo studies, we show that VNN1 activates a detrimental cascade of processes in Lats1/2PanKO epithelium, whereby 1) NFκB activation and 2) initiation of epithelial-to-mesenchymal transition (EMT) together override normal differentiation. We show that exogenous stimulation of VNN1 or NFκB can also trigger this cascade in WT pancreatic progenitors. These findings show that pancreas development requires active suppression of NFκB by LATS1/2 kinases to restrain a cell-autonomous transcriptional program and thereby allow for differentiation.
2019-06-21 | GSE126551 | GEO
Project description:Hippo signaling, an evolutionarily conserved pathway involved in organ size control, has been implicated to play key roles in developmental processes of various tissues, but its role in craniofacial development has not been largely explored. To examine the function of the Hippo signaling kinase cascade, we inactivated Hippo components Lats1 and Lats2 in the cranial neuroepithelium of mouse embryos using a Wnt1CreSOR driver. Double conditional knock out (DCKO) of Lats1/2 resulted in neural tube and craniofacial defects. Lats1/2 DCKO mutant embryos presented a minute head with delayed and defective neural tube closure. Furthermore, neuroepithelial cell polarity and cell integrity were disrupted within the cranial neural tube in Lats1/2 DCKO mutants. Embryonic neural tube RNA-seq revealed increased TGF-beta signaling in absence of Lats1/2. Moreover, markers of epithelial-to-mesenchymal transition (EMT) were upregulated in the cranial neural tube. Notably, modulation of Hippo signaling downstream effectors Yap and Taz prevented neuroepithelial defects, aberrant EMT, and TGF-beta dysregulation caused by Lats1/2 deficiency, indicating that Lats1/2 function via canonical Hippo-Yap pathway. Together, our findings revealed important roles for Hippo signaling kinases in pre-migratory neural crest EMT and migration.
2022-09-05 | GSE182721 | GEO
Project description: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 (Lats1/2PanKO) 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 Lats1/2PanKO. 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 Lats1/2PanKO 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.
| S-EPMC6668837 | biostudies-literature
Project description:The NfkB-pathway is activated early during acute pancreatitis. We investigated the influence on gene expression of two pancreas-specific deletions interfering with NfkB-activation. Pancreata from 8 week old mice were prepared, RNA was isolated and Affymetrix microarray expression analysis was performed.
2012-12-02 | E-MTAB-886 | biostudies-arrayexpress
Project description:Deregulated activity of the LATS tumor suppressors has broad implications on cellular and tissue homeostasis. We examined the consequences of downregulation of either LATS1 or LATS2 in breast cancer. Consistent with their proposed tumor suppressive roles, expression of both paralogs is significantly downregulated in human breast cancer, and loss of either paralog accelerated mammary tumorigenesis in mice. However, each paralog had a distinct impact on breast cancer. Thus, LATS2 depletion in luminal B tumors resulted in metabolic rewiring, with increased glycolysis and reduced PPARg signaling. Furthermore, pharmacological activation of PPARg elicited LATS2-dependent death in luminal B-derived cells. In contrast, LATS1 depletion augmented cancer cell plasticity, skewing luminal B tumors towards increased expression of basal-like features, in association with increased resistance to hormone therapy. Hence, these two closely related paralogs play distinct roles in protection against breast cancer; tumors with reduced expression of either LATS1 or LATS2 may rewire signaling networks differently and thus respond differently to anti-cancer treatments.
2018-10-28 | GSE116817 | GEO
Project description:Deregulated activity of the LATS tumor suppressors has broad implications on cellular and tissue homeostasis. We examined the consequences of downregulation of either LATS1 or LATS2 in breast cancer. Consistent with their proposed tumor suppressive roles, expression of both paralogs is significantly downregulated in human breast cancer, and loss of either paralog accelerated mammary tumorigenesis in mice. However, each paralog had a distinct impact on breast cancer. Thus, LATS2 depletion in luminal B tumors resulted in metabolic rewiring, with increased glycolysis and reduced PPARg signaling. Furthermore, pharmacological activation of PPARg elicited LATS2-dependent death in luminal B-derived cells. In contrast, LATS1 depletion augmented cancer cell plasticity, skewing luminal B tumors towards increased expression of basal-like features, in association with increased resistance to hormone therapy. Hence, these two closely related paralogs play distinct roles in protection against breast cancer; tumors with reduced expression of either LATS1 or LATS2 may rewire signaling networks differently and thus respond differently to anti-cancer treatments.
2018-10-28 | GSE116816 | GEO
Project description:Epithelial–mesenchymal transition (EMT) is known to be involved in cancer metastasis and pathogenesis. Metabolic re-wiring is now considered to be one of the hallmarks of cancer. In this study, we studied the metabolic changes during EMT in three breast EMT cell models with a proteomic approach. The study showed well-known changes during EMT including CDH1, CDH2, VIM, LGALS1, SERPINE1 and PKP3. It also suggested a list of dysregulated metabolic enzymes: SORD, TSTA3, FDFT1 and UGDH. UGDH had the biggest change and is associated with patient survival. We further studied the role of UGDH in EMT and found out knockdown of UGDH with siRNA can decrease the intracellular glycerophosphocholine level and it can also slow cell proliferation and invasion in mesenchymal cells. Besides, knockdown of UGDH downregulated the expression of a well-known EMT marker, SNAI1. PDGFRB is highly expressed in mesenchymal cells and PDGFD is highly secreted from mesenchymal cells. Knockdown of PDGFRB with siRNA downregulated UGDH potentially via NFkB.
2022-01-04 | PXD024164 | Pride
Project description:High-grade serous ovarian cancer (HGSOC) is the deadliest and most common subtype of ovarian cancer. Unfortunately, most patients develop recurrence and ultimately resistance to standard platinum chemotherapy. Large tumor suppressors LATS1 and LATS2, the core Hippo signaling kinases, have been implicated in various cancer types, including ovarian cancer. The mechanism by which LATS1/2 suppresses ovarian cancer progression is currently elusive, but the expression of LATS1/2 is frequently reduced or lost in these cancers. In this study, we demonstrate that the inactivation of LATS1/2 is sufficient to transform normal mouse ovarian epithelium into tumorigenic cells associated with increased cell proliferation, invasion and stemness and epithelial–mesenchymal transition (EMT) characteristics. Knockout of Lats1/2 in the epithelial cells also leads to higher expression levels of the immune checkpoint molecule PD-L1, suggesting a regulatory role of LATS1/2 in modulating immune responses and immune evasion. In addition to the loss of LATS1/2 activating the downstream transcriptional coactivators YAP and TAZ, PI3K-AKT activity was also increased, likely contributing to enhanced tumor proliferation and survival. The stimulatory effect of Lats1/2 knockout on cell proliferation can be partially reversed by treatment with the AKT inhibitor MK2206. Treatment with verteporfin, a potent inhibitor of YAP/TAZ, decreases ovarian tumor progression and reduces the activated AKT in the tumors. In summary, this study uncovers several biological mechanisms for the initiation of HGSOC and identifies LATS1/2 as potential prognostic indicators and therapeutic targets.
2025-03-18 | GSE291871 | GEO
Project description:Lats1/2 control TGF-beta directed EMT in the dorsal cranial neuroepithelium through YAP regulation
| PRJNA757609 | ENA
Project description:Lats1-/-;Lats2fl/fl;Alb-Cre pups and control pups were sacrificed at 1 day after birth Total mRNA obtained from livers in control and Lats1/2 deficient neonatal mice
2016-06-29 | E-GEOD-71872 | biostudies-arrayexpress