LATS1/2 inactivation drives distinct endothelial responses that contribute to the fibrotic remodeling of the lung
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE316804 | GEO | 2026/09/01
REPOSITORIES: GEO
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Project description:YAP/TAZ signaling is required for initiation of lung alveolar repair, yet previous studies in idiopathic pulmonary fibrosis (IPF) predicted increased YAP/TAZ signaling in alveolar epithelial cells (AECs). We investigated whether persistent YAP/TAZ AEC signaling contributes to failed epithelial repair and persistent fibrotic remodeling. In IPF lungs, we identified increased YAP+/TAZ+ AECs and increased transcriptional target expression. Pharmacological YAP/TAZ activation in human AEC organoids and in murine AT2 cell organoids generated with genetic Yap/Taz activation (YTactive) (via deletion of Hippo-kinases Stk3/4), resulted in phenotype shifts into aberrant transitional and airway-like states. Bleomycin injury of YTactive mice resulted in persistent fibrotic remodeling at 28- and 56-days post-bleomycin injury. Gene promoter activity associated with transitional cell markers (Krt19, Hopx, and Runx2) was increased in YTactive AT2 cells. Immunofluorescent staining showed a loss of AT2 associated Cebpa and increased Krt19 in YTactive lineage traced AT2 cells 28 days post-injury. Inhibition of Yap/Taz using Verteporfin resulted in improved lung repair in YTactive mouse lungs, including restored Cebpa and decreased Krt19+ transitional cells. These findings demonstrate sustained Yap/Taz activation drives abnormal alveolar repair and persistent fibrotic remodeling. Blocking aberrant persistent Yap/Taz activity promotes adaptive repair and has potential as a therapeutic strategy for pulmonary fibrosis.
2026-06-02 | GSE327565 | GEO
Project description:YAP/TAZ signaling is required for initiation of lung alveolar repair, yet previous studies in idiopathic pulmonary fibrosis (IPF) predicted increased YAP/TAZ signaling in alveolar epithelial cells (AECs). We investigated whether persistent YAP/TAZ AEC signaling contributes to failed epithelial repair and persistent fibrotic remodeling. In IPF lungs, we identified increased YAP+/TAZ+ AECs and increased transcriptional target expression. Pharmacological YAP/TAZ activation in human AEC organoids and in murine AT2 cell organoids generated with genetic Yap/Taz activation (YTactive) (via deletion of Hippo-kinases Stk3/4), resulted in phenotype shifts into aberrant transitional and airway-like states. Bleomycin injury of YTactive mice resulted in persistent fibrotic remodeling at 28- and 56-days post-bleomycin injury. Gene promoter activity associated with transitional cell markers (Krt19, Hopx, and Runx2) was increased in YTactive AT2 cells. Immunofluorescent staining showed a loss of AT2 associated Cebpa and increased Krt19 in YTactive lineage traced AT2 cells 28 days post-injury. Inhibition of Yap/Taz using Verteporfin resulted in improved lung repair in YTactive mouse lungs, including restored Cebpa and decreased Krt19+ transitional cells. These findings demonstrate sustained Yap/Taz activation drives abnormal alveolar repair and persistent fibrotic remodeling. Blocking aberrant persistent Yap/Taz activity promotes adaptive repair and has potential as a therapeutic strategy for pulmonary fibrosis.
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Project description:Analysis of genes enriched in MIXL1+ sorted cells during primitive streak induction identified Apelin receptor (APLNR), a highly conserved member of the G-protein coupled receptor family. Depending upon the growth factor conditions used for differentiation, APLNR+ cells identified both posterior mesodermal and anterior mesendodermal components of the primitive streak. APLNR+ cells isolated from mesodermal differentiated cultures were enriched in hematopoietic blast colony forming cells (Bl-CFCs) and the addition of Apelin peptide enhanced the frequency and growth of both hematopoietic colonies and hESC-derived endothelial cells. These studies identified APLNR as a marker of primitive streak-like cells differentiated from hESCs and defined a novel role for Apelin as a regulator of early human hematopoiesis.
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Project description:YAP and TAZ play oncogenic roles in various organs, but the role of YAP/TAZ activation in gastric cancer in vivo has been understudied. We investigated whether and how YAP/TAZ initiates gastric tumorigenesis in vivo and its significance in human gastric cancer. We studied Lats1fl/fl;Lats2fl/fl;Lgr5-CreER mice, which have activated YAP/TAZ in pyloric stem cells. Gastric tissues were collected and analyzed by histopathology and immunostaining. To scrutinize the molecular mechanisms, we performed RNA sequencing in gastric tissue samples. Tissue microarray and public transcriptome data were analyzed to investigate the importance of YAP/TAZ in human gastric cancer.
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Project description:We treated HUVEC with Apelin 13 or siRNA of Aplnr to investigate the impact of Apelin 13 and APLNR knockdown. We then performed gene expression profiling analysis using data obtained from RNA-seq of 7 different conditions.
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Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage derived sarcomas with poor prognosis. The molecular events underlying SC lineage cells-to-MPNST transformation remain elusive. Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Lats1/2 deficiency reprograms SCs to a cancerous, progenitor-like phenotype and promotes hyper-proliferation. Conversely, disruption of TAZ/YAP activity alleviates tumor burden in Lats1/2-deficient mice and inhibits human MPNST cell proliferation. Moreover, genome-wide target profiling reveals that TAZ/YAP-TEAD1 directly activates a set of oncogenic programs in SCs including PDGFR/RAF signaling. Co-targeting TAZ/YAP and PDGFR/RAF signaling efficaciously reduces tumorigenicity in Lats1/2-deficient tumors. Thus, our findings establish a previously unrecognized convergence between LATS1/2-TAZ/YAP pathway and MPNST pathogenesis, suggesting that combined inhibition of TAZ/YAP-PDGFR/RAF signaling may be beneficial in MPNSTs.
2018-02-13 | GSE99040 | GEO
Project description:Human cancer is often caused by dysfunctional developmental pathways, but such mechanisms do not always present clear opportunities for therapeutic intervention. This is exemplified by the Hippo tumor suppressor pathway, which is comprised of a kinase module that restrains the function of YAP/TAZ transcriptional coactivators; a pathway that becomes dysregulated in a wide array of human cancers. Hence, YAP/TAZ hyperactivation is a tumorigenic mechanism and a validated therapeutic target in oncology. In this study, we used a paralog co-targeting genetic screening strategy to identify the kinases MARK2/3 as co-dependencies of YAP/TAZ in diverse cancer contexts. We use biochemical and epistasis experiments to show that MARK2/3 phosphorylate and inhibit the activity of Hippo pathway components NF2, MST1/2, and MAP4Ks, which leads to indirect upstream control of LATS1/2 activity. In addition, MARK2/3 directly phosphorylate YAP/TAZ to shield these coactivators from LATS1/2-mediated inhibition. The net consequence of this multi-level regulation is that YAP/TAZ-dependent human cancers have an absolute requirement for MARK2/3 catalytic activity to sustain tumor cell proliferation and viability. To simulate therapeutic targeting of MARK2/3 in vivo, we adapted the EPIYA-repeat region of the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show exerts potent anti-tumor activity via on-target mechanisms. Together, these findings reveal MARK2/3 as an obligate catalytic requirement for YAP/TAZ function in human cancer; kinase targets that may allow for novel pharmacology that restores Hippo-mediated tumor suppression.
2024-07-25 | PXD054192 | Pride
Project description:Human cancer is often caused by dysfunctional developmental pathways, but such mechanisms do not always present clear opportunities for therapeutic intervention. This is exemplified by the Hippo tumor suppressor pathway, which is comprised of a kinase module that restrains the function of YAP/TAZ transcriptional coactivators; a pathway that becomes dysregulated in a wide array of human cancers. Hence, YAP/TAZ hyperactivation is a tumorigenic mechanism and a validated therapeutic target in oncology. In this study, we used a paralog co-targeting genetic screening strategy to identify the kinases MARK2/3 as co-dependencies of YAP/TAZ in diverse cancer contexts. We use biochemical and epistasis experiments to show that MARK2/3 phosphorylate and inhibit the activity of Hippo pathway components NF2, MST1/2, and MAP4Ks, which leads to indirect upstream control of LATS1/2 activity. In addition, MARK2/3 directly phosphorylate YAP/TAZ to shield these coactivators from LATS1/2-mediated inhibition. The net consequence of this multi-level regulation is that YAP/TAZ-dependent human cancers have an absolute requirement for MARK2/3 catalytic activity to sustain tumor cell proliferation and viability. To simulate therapeutic targeting of MARK2/3 in vivo, we adapted the EPIYA-repeat region of the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show exerts potent anti-tumor activity via on-target mechanisms. Together, these findings reveal MARK2/3 as an obligate catalytic requirement for YAP/TAZ function in human cancer; kinase targets that may allow for novel pharmacology that restores Hippo-mediated tumor suppression.
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Project description:The transcriptional coregulators YAP and TAZ control tissue homeostasis as downstream effectors of the Hippo signaling pathway. The molecular mechanisms by which they regulate cell differentiation or dedifferentiation have remained unclear, however. Here we reveal how YAP/TAZ regulates the transcription and genomic activity of the adipocyte lineage-specification factor PPARγ at the chromatin level. TAZ binds to the Pparg2 genomic region and to PPARγ target gene enhancers, thereby inducing chromatin reprogramming and transcriptional repression. Binding to TEAD transcription factors is essential for this repressive action of TAZ, but direct protein interaction with PPARγ via the WW domain of TAZ is not. Single-nucleus genomic analyses of mouse adipose tissue revealed that YAP/TAZ hyperactivation drives extensive epigenetic changes and the dedifferentiation of adipocytes. Collectively, our findings indicate that YAP/TAZ determine adipocyte fate by modulating the expression of a key transcription factor and the enhancer landscape of its target genes.
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Project description:The transcriptional coregulators YAP and TAZ control tissue homeostasis as downstream effectors of the Hippo signaling pathway. The molecular mechanisms by which they regulate cell differentiation or dedifferentiation have remained unclear, however. Here we reveal how YAP/TAZ regulates the transcription and genomic activity of the adipocyte lineage-specification factor PPARγ at the chromatin level. TAZ binds to the Pparg2 genomic region and to PPARγ target gene enhancers, thereby inducing chromatin reprogramming and transcriptional repression. Binding to TEAD transcription factors is essential for this repressive action of TAZ, but direct protein interaction with PPARγ via the WW domain of TAZ is not. Single-nucleus genomic analyses of mouse adipose tissue revealed that YAP/TAZ hyperactivation drives extensive epigenetic changes and the dedifferentiation of adipocytes. Collectively, our findings indicate that YAP/TAZ determine adipocyte fate by modulating the expression of a key transcription factor and the enhancer landscape of its target genes.
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