Publications by authors named "Randy L Johnson"

106 Publications

A genome-wide library of MADM mice for single-cell genetic mosaic analysis.

Cell Rep 2021 Jun;35(12):109274

Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria. Electronic address:

Mosaic analysis with double markers (MADM) offers one approach to visualize and concomitantly manipulate genetically defined cells in mice with single-cell resolution. MADM applications include the analysis of lineage, single-cell morphology and physiology, genomic imprinting phenotypes, and dissection of cell-autonomous gene functions in vivo in health and disease. Yet, MADM can only be applied to <25% of all mouse genes on select chromosomes to date. To overcome this limitation, we generate transgenic mice with knocked-in MADM cassettes near the centromeres of all 19 autosomes and validate their use across organs. With this resource, >96% of the entire mouse genome can now be subjected to single-cell genetic mosaic analysis. Beyond a proof of principle, we apply our MADM library to systematically trace sister chromatid segregation in distinct mitotic cell lineages. We find striking chromosome-specific biases in segregation patterns, reflecting a putative mechanism for the asymmetric segregation of genetic determinants in somatic stem cell division.
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http://dx.doi.org/10.1016/j.celrep.2021.109274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317686PMC
June 2021

Dysregulation of PI3K and Hippo signaling pathways synergistically induces chronic pancreatitis via CTGF upregulation.

J Clin Invest 2021 Jul;131(13)

Department of Gastroenterology and Hepatology and.

The role of PI3K and Hippo signaling in chronic pancreatitis (CP) pathogenesis is unclear. Therefore, we assessed the involvement of these pathways in CP by examining the PI3K and Hippo signaling components PTEN and SAV1, respectively. We observed significant decreases in pancreatic PTEN and SAV1 levels in 2 murine CP models: repeated cerulein injection and pancreatic ductal ligation. Additionally, pancreas-specific deletion of Pten and Sav1 (DKO) induced CP in mice. Pancreatic connective tissue growth factor (CTGF) was markedly upregulated in both CP models and DKO mice, and pancreatic CCAAT/enhancer-binding protein-α (CEBPA) expression was downregulated in the CP models. Interestingly, in pancreatic acinar cells (PACs), CEBPA knockdown reduced PTEN and SAV1 and increased CTGF levels in vitro. Furthermore, CEBPA knockdown in PACs induced acinar-to-ductal metaplasia and activation of cocultured macrophages and pancreatic stellate cells. These results were mitigated by CTGF inhibition. CP in DKO mice was also ameliorated by Ctgf gene deletion, and cerulein-induced CP was alleviated by antibody-mediated CTGF neutralization. Finally, we observed significantly decreased PTEN, SAV1, and CEBPA and increased CTGF levels in human CP tissues compared with nonpancreatitis tissues. Taken together, our results indicate that dysregulation of PI3K and Hippo signaling induces CP via CTGF upregulation.
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http://dx.doi.org/10.1172/JCI143414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245178PMC
July 2021

Loss of ARID1A activates mTOR signaling and SOX9 in gastric adenocarcinoma-rationale for targeting deficiency.

Gut 2021 Mar 30. Epub 2021 Mar 30.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Background: Gastric adenocarcinoma (GAC) is a lethal disease with limited therapeutic options. Genetic alterations in chromatin remodelling gene AT-rich interactive domain 1A () and mTOR pathway activation occur frequently in GAC. Targeting the mechanistic target of rapamycin (mTOR) pathway in unselected patients has failed to show survival benefit. A deeper understanding of GAC might identify a subset that can benefit from mTOR inhibition.

Methods: Genomic alterations in were analysed in GAC. Mouse gastric epithelial cells from and wild-type mice were used to determine the activation of oncogenic genes due to loss of Arid1A. Functional studies were performed to determine the significance of loss of ARID1A and the sensitivity of ARID1A-deficient cancer cells to mTOR inhibition in GAC.

Results: More than 30% of GAC cases had alterations (mutations or deletions) of ARID1A and ARID1A expression was negatively associated with phosphorylation of S6 and SOX9 in GAC tissues and patient-derived xenografts (PDXs). Activation of mTOR signalling (increased pS6) and SOX9 nuclear expression were strongly increased in Arid1A mouse gastric tissues which could be curtailed by RAD001, an mTOR inhibitor. Knockdown of ARID1A in GAC cell lines increased pS6 and nuclear SOX9 and increased sensitivity to an mTOR inhibitor which was further amplified by its combination with fluorouracil both in vitro and in vivo in PDXs.

Conclusions: The loss of ARID1A activates pS6 and SOX9 in GAC, which can be effectively targeted by an mTOR inhibitor. Therefore, our studies suggest a new therapeutic strategy of clinically targeting the mTOR pathway in patients with GAC with ARID1A deficiency.
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http://dx.doi.org/10.1136/gutjnl-2020-322660DOI Listing
March 2021

Hippo signalling maintains ER expression and ER breast cancer growth.

Nature 2021 03 3;591(7848):E1-E10. Epub 2021 Mar 3.

Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.

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http://dx.doi.org/10.1038/s41586-020-03131-5DOI Listing
March 2021

Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma.

Gut 2021 Jan 24. Epub 2021 Jan 24.

Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Objective: Gastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial.

Methods: Extensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation.

Results: Overexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes () that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity.

Conclusions: Our preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.
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http://dx.doi.org/10.1136/gutjnl-2020-321175DOI Listing
January 2021

YAP1 mediates gastric adenocarcinoma peritoneal metastases that are attenuated by YAP1 inhibition.

Gut 2021 01 27;70(1):55-66. Epub 2020 Apr 27.

Department of Gastrointestinal Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA

Objective: Peritoneal carcinomatosis (PC; malignant ascites or implants) occurs in approximately 45% of advanced gastric adenocarcinoma (GAC) patients and associated with a poor survival. The molecular events leading to PC are unknown. The yes-associated protein 1 () oncogene has emerged in many tumour types, but its clinical significance in PC is unclear. Here, we investigated the role of YAP1 in PC and its potential as a therapeutic target.

Methods: Patient-derived PC cells, patient-derived xenograft (PDX) and patient-derived orthotopic (PDO) models were used to study the function of YAP1 in vitro and in vivo. Immunofluorescence and immunohistochemical staining, RNA sequencing (RNA-Seq) and single-cell RNA-Seq (sc-RNA-Seq) were used to elucidate the expression of YAP1 and PC cell heterogeneity. LentiCRISPR/Cas9 knockout of YAP1 and a YAP1 inhibitor were used to dissect its role in PC metastases.

Results: YAP1 was highly upregulated in PC tumour cells, conferred cancer stem cell (CSC) properties and appeared to be a metastatic driver. Dual staining of YAP1/EpCAM and sc-RNA-Seq revealed that PC tumour cells were highly heterogeneous, YAP1 PC cells had CSC-like properties and easily formed PDX/PDO tumours but also formed PC in mice, while genetic knockout YAP1 significantly slowed tumour growth and eliminated PC in PDO model. Additionally, pharmacologic inhibition of YAP1 specifically reduced CSC-like properties and suppressed tumour growth in YAP1 PC cells especially in combination with cytotoxics in vivo PDX model.

Conclusions: YAP1 is essential for PC that is attenuated by YAP1 inhibition. Our data provide a strong rationale to target YAP1 in clinic for GAC patients with PC.
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http://dx.doi.org/10.1136/gutjnl-2019-319748DOI Listing
January 2021

Lats1/2 Sustain Intestinal Stem Cells and Wnt Activation through TEAD-Dependent and Independent Transcription.

Cell Stem Cell 2020 05 6;26(5):675-692.e8. Epub 2020 Apr 6.

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA. Electronic address:

Intestinal homeostasis is tightly regulated by complex yet poorly understood signaling networks. Here, we demonstrate that Lats1/2, the core Hippo kinases, are essential to maintain Wnt pathway activity and intestinal stem cells. Lats1/2 deletion leads to loss of intestinal stem cells but drives Wnt-uncoupled crypt expansion. To explore the function of downstream transcriptional enhanced associate domain (TEAD) transcription factors, we identified a selective small-molecule reversible inhibitor of TEAD auto-palmitoylation that directly occupies its lipid-binding site and inhibits TEAD-mediated transcription in vivo. Combining this chemical tool with genetic and proteomics approaches, we show that intestinal Wnt inhibition by Lats deletion is Yes-associated protein (YAP)/transcriptional activator with PDZ-binding domain (TAZ) dependent but TEAD independent. Mechanistically, nuclear YAP/TAZ interact with Groucho/Transducin-Like Enhancer of Split (TLE) to block Wnt/T-cell factor (TCF)-mediated transcription, and dual inhibition of TEAD and Lats suppresses Wnt-uncoupled Myc upregulation and epithelial over-proliferation in Adenomatous polyposis coli (APC)-mutated intestine. Our studies highlight a pharmacological approach to inhibit TEAD palmitoylation and have important implications for targeting Wnt and Hippo signaling in human malignancies.
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http://dx.doi.org/10.1016/j.stem.2020.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310193PMC
May 2020

Targeting Hippo coactivator YAP1 through BET bromodomain inhibition in esophageal adenocarcinoma.

Mol Oncol 2020 06 7;14(6):1410-1426. Epub 2020 Apr 7.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Hippo/YAP1 signaling is a major regulator of organ size, cancer stemness, and aggressive phenotype. Thus, targeting YAP1 may provide a novel therapeutic strategy for tumors with high YAP1 expression in esophageal cancer (EC). Chromatin immunoprecipitation (ChiP) and quantitative ChiP-PCR were used to determine the regulation of the chromatin remodeling protein bromodomain-containing protein 4 (BRD4) on YAP1. The role of the bromodomain and extraterminal motif (BET) inhibitor JQ1, an established BRD4 inhibitor, on inhibition of YAP1 in EC cells was dissected using western blot, immunofluorescence, qPCR, and transient transfection. The antitumor activities of BET inhibitor were further examined by variety of functional assays, cell proliferation (MTS), tumorsphere, and ALDH1+ labeling in vitro and in vivo. Here, we show that BRD4 regulates YAP1 expression and transcription. ChiP assays revealed that BRD4 directly occupies YAP1 promoter and that JQ1 robustly blocks BRD4 binding to the YAP1 promoter. Consequently, JQ1 strongly suppresses constitutive or induced YAP1 expression and transcription in EC cells and YAP1/Tead downstream transcriptional activity. Intriguingly, radiation-resistant cells that acquire strong cancer stem cell traits and an aggressive phenotype can be effectively suppressed by JQ1 as assessed by cell proliferation, tumorsphere formation, and reduction in the ALDH1+ cells. Moreover, effects of JQ1 are synergistically amplified by the addition of docetaxel in vitro and in vivo. Our results demonstrate that BRD4 is a critical regulator of Hippo/YAP1 signaling and that BRD4 inhibitor JQ1 represents a new class of inhibitor of Hippo/YAP1 signaling, primarily targeting YAP1 high and therapy-resistant cancer cells enriched with cancer stem cell properties.
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http://dx.doi.org/10.1002/1878-0261.12667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266288PMC
June 2020

YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression.

Cell Rep 2019 12;29(10):3200-3211.e4

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address:

Uveal melanoma (UM), the most common ocular malignancy, is characterized by GNAQ/11 mutations. Hippo/YAP and Ras/mitogen-activated protein kinase (MAPK) emerge as two important signaling pathways downstream of G protein alpha subunits of the Q class (GαQ/11)-mediated transformation, although whether and how they contribute to UM genesis in vivo remain unclear. Here, we adapt an adeno-associated virus (AAV)-based ocular injection method to directly deliver Cre recombinase into the mouse uveal tract and demonstrate that Lats1/2 kinases suppress UM formation specifically in uveal melanocytes. We find that genetic activation of YAP, but not Kras, is sufficient to initiate UM. We show that YAP/TAZ activation induced by Lats1/2 deletion cooperates with Kras to promote UM progression via downstream transcriptional reinforcement. Furthermore, dual inhibition of YAP/TAZ and Ras/MAPK synergizes to suppress oncogenic growth of human UM cells. Our data highlight the functional significance of Lats-YAP/TAZ in UM initiation and progression in vivo and suggest combination inhibition of YAP/TAZ and Ras/MAPK as a new therapeutic strategy for UM.
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http://dx.doi.org/10.1016/j.celrep.2019.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871510PMC
December 2019

PPARδ Interacts with the Hippo Coactivator YAP1 to Promote SOX9 Expression and Gastric Cancer Progression.

Mol Cancer Res 2020 03 3;18(3):390-402. Epub 2019 Dec 3.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Despite established functions of PPARδ in lipid metabolism and tumorigenesis, the mechanisms underlying its role in gastric cancer are undefined. Here, we demonstrate that SOX9 was dramatically induced by stably expressing PPARδ and by its agonist GW501516 in human gastric cancer cell lines. PPARδ knockdown in patient-derived gastric cancer cells dramatically reduced SOX9 expression and transcriptional activity, with corresponding decreases in invasion and tumor sphere formation. Mechanistically, PPARδ induced SOX9 transcription through direct interaction with and activation of the Hippo coactivator YAP1. PPARδ-YAP1 interaction occurred via the C-terminal domain of YAP1, and both TEAD- and PPARE-binding sites were required for SOX9 induction. Notably, CRISPR/Cas9-mediated genetic ablation of YAP1 or SOX9 abolished PPARδ-mediated oncogenic functions. Finally, expression of PPARδ, YAP1, and SOX9 were significantly correlated with each other and with poor survival in a large cohort of human gastric cancer tissues. Thus, these findings elucidate a novel mechanism by which PPARδ promotes gastric tumorigenesis through interaction with YAP1 and highlights the PPARδ/YAP1/SOX9 axis as a novel therapeutic target in human gastric cancer. IMPLICATIONS: Our discovery of a new model supports a distinct paradigm for PPARδ and a crucial oncogenic function of PPARδ in gastric cancer through convergence on YAP1/TEAD signaling. Therefore, PPARδ/YAP1/SOX9 axis could be a novel therapeutic target that can be translated into clinics.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0895DOI Listing
March 2020

Activation of the intrinsic fibroinflammatory program in adult pancreatic acinar cells triggered by Hippo signaling disruption.

PLoS Biol 2019 09 12;17(9):e3000418. Epub 2019 Sep 12.

Department of Cell Systems & Anatomy, UT Health San Antonio, San Antonio, Texas, United States of America.

Damaged acinar cells play a passive role in activating pancreatic stellate cells (PSCs) via recruitment of immune cells that subsequently activate PSCs. However, whether acinar cells directly contribute to PSC activation is unknown. Here, we report that the Hippo pathway, a well-known regulator of proliferation, is essential for suppression of expression of inflammation and fibrosis-associated genes in adult pancreatic acinar cells. Hippo inactivation in acinar cells induced yes-associated protein 1 (YAP1)/transcriptional coactivator with PDZ binding motif (TAZ)-dependent, irreversible fibrosis and inflammation, which was initiated by Hippo-mediated acinar-stromal communications and ameliorated by blocking YAP1/TAZ target connective tissue growth factor (CTGF). Hippo disruption promotes acinar cells to secrete fibroinflammatory factors and induce stromal activation, which precedes acinar proliferation and metaplasia. We found that Hippo disruption did not induce cell-autonomous proliferation but primed acinar cells to exogenous pro-proliferative stimuli, implying a well-orchestrated scenario in which Hippo signaling acts as an intrinsic link to coordinate fibroinflammatory response and proliferation for maintenance of the tissue integrity. Our findings suggest that the fibroinflammatory program in pancreatic acinar cells is suppressed under normal physiological conditions. While transient activation of inflammatory gene expression during tissue injury may contribute to the control of damage and tissue repair, its persistent activation may result in tissue fibrosis and failure of regeneration.
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http://dx.doi.org/10.1371/journal.pbio.3000418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742234PMC
September 2019

Hippo signaling and epithelial cell plasticity in mammalian liver development, homeostasis, injury and disease.

Authors:
Randy L Johnson

Sci China Life Sci 2019 Dec 26;62(12):1609-1616. Epub 2019 Aug 26.

Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, 6767 Bertner Ave, Houston, TX, 77030, USA.

A traditional view of cellular differentiation is unidirectional: progenitor cells adopt specific fates in response to environmental cues resulting in deployment of cell-specific gene expression programs and acquisition of unique differentiated cellular properties such as production of structural and functional proteins that define individual cell types. In both development and in tissue repair stem and progenitor cells are thought to both self-renew to maintain the pool of precursors and to expand to give rise to transient amplifying and differentiated cell types. Recently, however, it has become appreciated that differentiated cell types can be reprogrammed to adopt progenitor and stem cell properties. In the case of epithelial cells in the mammalian liver, hepatocytes and biliary epithelial cells there is a significant degree of plasticity between these lineages that has been implicated in mechanisms of tissue repair and in liver pathologies such as cancer. Recent studies have highlighted the role of Hippo signaling, an emerging growth control and tumor suppressor pathway, in regulating epithelial cell plasticity in the mammalian liver and in this review, the role of cellular plasticity and Hippo signaling in regulating normal and abnormal tissue responses in the mammalian liver will be discussed.
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http://dx.doi.org/10.1007/s11427-018-9510-3DOI Listing
December 2019

and are required for ovarian granulosa cell fate maintenance.

FASEB J 2019 10 3;33(10):10819-10832. Epub 2019 Jul 3.

Département de Biomédecine Vétérinaire, Centre de Recherche en Reproduction et Fertilité, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec, Canada.

Recent reports suggest that the Hippo signaling pathway influences ovarian follicle development; however, its exact roles remain unknown. Here, we examined the ovarian functions of the Hippo kinases large tumor suppressors (LATS)1 and 2, which serve to inactivate the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Inactivation of in murine granulosa cells either or resulted in a loss of granulosa cell morphology, function, and gene expression. Mutant cells further underwent changes in structure and gene expression suggestive of epithelial-to-mesenchymal transition and transdifferentiation into multiple lineages. , granulosa cell-specific loss of caused the ovarian parenchyma to be mostly replaced by bone tissue and seminiferous tubule-like structures. Transdifferentiation into Sertoli-like cells and osteoblasts was attributed in part to the increased recruitment of YAP and TAZ to the promoters of sex-determining region Y box 9 and bone γ-carboxyglutamate protein, key mediators of male sex determination and osteogenesis, respectively. Together, these results demonstrate for the first time a critical role for in the maintenance of the granulosa cell genetic program and further highlight the remarkable plasticity of granulosa cells.-Tsoi, M., Morin, M., Rico, C., Johnson, R. L., Paquet, M., Gévry, N., Boerboom, D. and are required for ovarian granulosa cell fate maintenance.
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http://dx.doi.org/10.1096/fj.201900609RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766663PMC
October 2019

Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response.

Gut 2020 01 6;69(1):18-31. Epub 2019 Jun 6.

Epidemiology, UT MDACC, Houston, Texas, USA.

Objective: Peritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC's development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets.

Design: We performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs.

Results: We identified distinct alterations in PC versus primary GACs, such as more frequent mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in and , higher level of 'clock-like' mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: 'mesenchymal-like' and 'epithelial-like' with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive 'mesenchymal-like' subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-β as potential therapeutic immune targets.

Conclusions: We have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics.
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http://dx.doi.org/10.1136/gutjnl-2018-318070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943252PMC
January 2020

Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade.

Elife 2019 03 26;8. Epub 2019 Mar 26.

Centre for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, United Kingdom.

SOX2 positive pituitary stem cells (PSCs) are specified embryonically and persist throughout life, giving rise to all pituitary endocrine lineages. We have previously shown the activation of the STK/LATS/YAP/TAZ signalling cascade in the developing and postnatal mammalian pituitary. Here, we investigate the function of this pathway during pituitary development and in the regulation of the SOX2 cell compartment. Through loss- and gain-of-function genetic approaches, we reveal that restricting YAP/TAZ activation during development is essential for normal organ size and specification from SOX2+ PSCs. Postnatal deletion of LATS kinases and subsequent upregulation of YAP/TAZ leads to uncontrolled clonal expansion of the SOX2+ PSCs and disruption of their differentiation, causing the formation of non-secreting, aggressive pituitary tumours. In contrast, sustained expression of YAP alone results in expansion of SOX2+ PSCs capable of differentiation and devoid of tumourigenic potential. Our findings identify the LATS/YAP/TAZ signalling cascade as an essential component of PSC regulation in normal pituitary physiology and tumourigenesis.
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http://dx.doi.org/10.7554/eLife.43996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461440PMC
March 2019

Macrophage achieves self-protection against oxidative stress-induced ageing through the Mst-Nrf2 axis.

Nat Commun 2019 02 14;10(1):755. Epub 2019 Feb 14.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.

Reactive oxygen species (ROS) production in phagocytes is a major defense mechanism against pathogens. However, the cellular self-protective mechanism against such potential damage from oxidative stress remains unclear. Here we show that the kinases Mst1 and Mst2 (Mst1/2) sense ROS and maintain cellular redox balance by modulating the stability of antioxidant transcription factor Nrf2. Site-specific ROS release recruits Mst1/2 from the cytosol to the phagosomal or mitochondrial membrane, with ROS subsequently activating Mst1/2 to phosphorylate kelch like ECH associated protein 1 (Keap1) and prevent Keap1 polymerization, thereby blocking Nrf2 ubiquitination and degradation to protect cells against oxidative damage. Treatment with the antioxidant N-acetylcysteine disrupts ROS-induced interaction of Mst1/2 with phagosomes or mitochondria, and thereby diminishes the Mst-Nrf2 signal. Consistently, loss of Mst1/2 results in increased oxidative injury, phagocyte ageing and death. Thus, our results identify the Mst-Nrf2 axis as an important ROS-sensing and antioxidant mechanism during an antimicrobial response.
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http://dx.doi.org/10.1038/s41467-019-08680-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376064PMC
February 2019

FGF15 Activates Hippo Signaling to Suppress Bile Acid Metabolism and Liver Tumorigenesis.

Dev Cell 2019 02 7;48(4):460-474.e9. Epub 2019 Feb 7.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; Cancer Research Center of Xiamen University, Xiamen, Fujian 361102, China. Electronic address:

The external factors that modulate Hippo signaling remain elusive. Here, we report that FGF15 activates Hippo signaling to suppress bile acid metabolism, liver overgrowth, and tumorigenesis. FGF15 is induced by FXR in ileal enterocytes in response to increased amounts of intestinal bile. We found that circulating enterohepatic FGF15 stimulates hepatic receptor FGFR4 to recruit and phosphorylate NF2, which relieves the inhibitory effect of Raf on the Hippo kinases Mst1/2, thereby switching FGFR4's role from pro-oncogenic to anti-tumor signaling. The activated Mst1/2 subsequently phosphorylates and stabilizes SHP to downregulate the key bile acid-synthesis enzyme Cyp7a1 expression, thereby limiting bile acid synthesis. In contrast, Mst1/2 deficiency impairs bile acid metabolism and remarkably increases Cyp7a1 expression and bile acid production. Importantly, pharmacological depletion of intestinal bile abrogates Mst1/2-mutant-driven liver overgrowth and oncogenesis. Therefore, FGF15-Hippo signaling along the gut-liver axis acts as a sensor of bile acid availability to restrain liver size and tumorigenesis.
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http://dx.doi.org/10.1016/j.devcel.2018.12.021DOI Listing
February 2019

YAP1-Mediated CDK6 Activation Confers Radiation Resistance in Esophageal Cancer - Rationale for the Combination of YAP1 and CDK4/6 Inhibitors in Esophageal Cancer.

Clin Cancer Res 2019 04 18;25(7):2264-2277. Epub 2018 Dec 18.

Department of Gastrointestinal Medical Oncology, U.T.MD. Anderson Cancer Center, Houston, Texas.

Purpose: Esophageal cancer is a lethal disease that is often resistant to therapy. Alterations of YAP1 and CDK6 are frequent in esophageal cancer. Deregulation of both molecules may be responsible for therapy resistance.

Experimental Design: Expressions of YAP1 and CDK6 were examined in esophageal cancer cells and tissues using immunoblotting and immunohistochemistry. YAP1 expression was induced in esophageal cancer cells to examine YAP1-mediated CDK6 activation and its association with radiation resistance. Pharmacologic and genetic inhibitions of YAP1 and CDK6 were performed to dissect the mechanisms and assess the antitumor effects and .

Results: YAP1 expression was positively associated with CDK6 expression in resistant esophageal cancer tissues and cell lines. YAP1 overexpression upregulated CDK6 expression and transcription, and promoted radiation resistance, whereas treatment with the YAP1 inhibitor, CA3, strongly suppressed YAP1 and CDK6 overexpression, reduced Rb phosphorylation, as well as sensitized radiation-resistant/YAP1 esophageal cancer cells to irradiation. CDK4/6 inhibitor, LEE011, and knock down of CDK6 dramatically inhibited expression of YAP1 and sensitized resistant esophageal cancer cells to irradiation indicating a positive feed-forward regulation of YAP1 by CDK6. In addition, suppression of both the YAP1 and CDK6 pathways by the combination of CA3 and LEE011 significantly reduced esophageal cancer cell growth and cancer stem cell population (ALDH1 and CD133 ), sensitized cells to irradiation, and showed a strong antitumor effect against radiation-resistant esophageal cancer cells.

Conclusions: Our results document that a positive crosstalk between the YAP1 and CDK6 pathways plays an important role in conferring radiation resistance to esophageal cancer cells. Targeting both YAP1 and CDK6 pathways could be a novel therapeutic strategy to overcome resistance in esophageal cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1029DOI Listing
April 2019

The Hippo Pathway Prevents YAP/TAZ-Driven Hypertranscription and Controls Neural Progenitor Number.

Dev Cell 2018 12 25;47(5):576-591.e8. Epub 2018 Oct 25.

Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

The Hippo pathway controls the activity of YAP/TAZ transcriptional coactivators through a kinase cascade. Despite the critical role of this pathway in tissue growth and tumorigenesis, it remains unclear how YAP/TAZ-mediated transcription drives proliferation. By analyzing the effects of inactivating LATS1/2 kinases, the direct upstream inhibitors of YAP/TAZ, on mouse brain development and applying cell-number-normalized transcriptome analyses, we discovered that YAP/TAZ activation causes a global increase in transcription activity, known as hypertranscription, and upregulates many genes associated with cell growth and proliferation. In contrast, conventional read-depth-normalized RNA-sequencing analysis failed to detect the scope of the transcriptome shift and missed most relevant gene ontologies. Following a transient increase in proliferation, however, hypertranscription in neural progenitors triggers replication stress, DNA damage, and p53 activation, resulting in massive apoptosis. Our findings reveal a significant impact of YAP/TAZ activation on global transcription activity and have important implications for understanding YAP/TAZ function.
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http://dx.doi.org/10.1016/j.devcel.2018.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296252PMC
December 2018

Hippo Pathway Kinase Mst1 Is Required for Long-Lived Humoral Immunity.

J Immunol 2019 01 26;202(1):69-78. Epub 2018 Nov 26.

Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada;

The protein kinase Mst1 is a key component of the evolutionarily conserved Hippo pathway that regulates cell survival, proliferation, differentiation, and migration. In humans, Mst1 deficiency causes primary immunodeficiency. Patients with MST1-null mutations show progressive loss of naive T cells but, paradoxically, mildly elevated serum Ab titers. Nonetheless, the role of Mst1 in humoral immunity remains poorly understood. In this study, we found that early T cell-dependent IgG1 responses in young adult Mst1-deficient mice were largely intact with signs of impaired affinity maturation. However, the established Ag-specific IgG1 titers in Mst1-deficient mice decayed more readily because of a loss of Ag-specific but not the overall bone marrow plasma cells. Despite the impaired affinity and longevity of Ag-specific Abs, Mst1-deficient mice produced plasma cells displaying apparently normal maturation markers with intact migratory and secretory capacities. Intriguingly, in immunized Mst1-deficient mice, T follicular helper cells were hyperactive, expressing higher levels of IL-21, IL-4, and surface CD40L. Accordingly, germinal center B cells progressed more rapidly into the plasma cell lineage, presumably forgoing rigorous affinity maturation processes. Importantly, Mst1-deficient mice had elevated levels of CD138Blimp1 splenic plasma cell populations, yet the size of the bone marrow plasma cell population remained normal. Thus, overproduced low-affinity plasma cells from dysregulated germinal centers seem to underlie humoral immune defects in Mst1-deficiency. Our findings imply that vaccination of Mst1-deficient human patients, even at the early stage of life, may fail to establish long-lived high-affinity humoral immunity and that prophylactic Ab replacement therapy can be beneficial to the patients.
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http://dx.doi.org/10.4049/jimmunol.1701407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310088PMC
January 2019

LATS1 and LATS2 suppress breast cancer progression by maintaining cell identity and metabolic state.

Life Sci Alliance 2018 Oct 30;1(5):e201800171. Epub 2018 Oct 30.

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

Deregulated activity of LArge Tumor Suppressor (LATS) tumor suppressors has broad implications on cellular and tissue homeostasis. We examined the consequences of down-regulation of either LATS1 or LATS2 in breast cancer. Consistent with their proposed tumor suppressive roles, expression of both paralogs was significantly down-regulated 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 peroxisome proliferator-activated receptor γ (PPARγ) signaling. Furthermore, pharmacological activation of PPARγ 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 anticancer treatments.
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http://dx.doi.org/10.26508/lsa.201800171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238411PMC
October 2018

The signaling protein Wnt5a promotes TGFβ1-mediated macrophage polarization and kidney fibrosis by inducing the transcriptional regulators Yap/Taz.

J Biol Chem 2018 12 17;293(50):19290-19302. Epub 2018 Oct 17.

From the Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, 210003 Jiangsu, China and

M2 macrophage polarization is known to underlie kidney fibrosis. We previously reported that most of the members of the Wnt family of signaling proteins are induced in fibrotic kidneys. Dysregulation of the signaling protein Wnt5a is associated with fibrosis, but little is known about the role of Wnt5a in regulating M2 macrophage activation that results in kidney fibrosis. Here, using murine Raw 264.7 cells and bone marrow-derived macrophages, we found that Wnt5a enhanced transforming growth factor β1 (TGFβ1)-induced macrophage M2 polarization as well as expression of the transcriptional regulators Yes-associated protein (Yap)/transcriptional coactivator with PDZ-binding motif (Taz). Verteporfin blockade of Yap/Taz inhibited both Wnt5a- and TGFβ1-induced macrophage M2 polarization. In mouse models of kidney fibrosis, shRNA-mediated knockdown of Wnt5a expression diminished kidney fibrosis, macrophage Yap/Taz expression, and M2 polarization. Moreover, genetic ablation of Taz in macrophages attenuated kidney fibrosis and macrophage M2 polarization in mice. Collectively, these results indicate that Wnt5a promotes kidney fibrosis by stimulating Yap/Taz-mediated macrophage M2 polarization.
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http://dx.doi.org/10.1074/jbc.RA118.005457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302175PMC
December 2018

Molecular profiling of nonalcoholic fatty liver disease-associated hepatocellular carcinoma using SB transposon mutagenesis.

Proc Natl Acad Sci U S A 2018 10 16;115(44):E10417-E10426. Epub 2018 Oct 16.

Genetics Department, The University of Texas MD Anderson Cancer Center, Houston, TX 77030

Nonalcoholic fatty liver disease (NAFLD) is the fastest rising cause of hepatocellular carcinoma (HCC) in Western countries; however, the molecular mechanisms that cause NAFLD-HCC remain elusive. To identify molecular drivers of NAFLD-HCC, we performed Sleeping Beauty (SB) transposon mutagenesis screens in liver-specific Pten knockout and in high-fat diet-fed mice, which are murine models of NAFLD-HCC. SB mutagenesis accelerated liver tumor formation in both models and identified 588 and 376 candidate cancer genes (CCGs), respectively; 257 CCGs were common to both screens and were enriched in signaling pathways known to be important for human HCC. Comparison of these CCGs with those identified in a previous SB screen of hepatitis B virus-induced HCC identified a core set of 141 CCGs that were mutated in all screens. Forty-one CCGs appeared specific for NAFLD-HCC, including Sav1, a component of the Hippo signaling pathway and the most frequently mutated gene identified in both NAFLD-HCC screens. Liver-specific deletion of Sav1 was found to promote hepatic lipid accumulation, apoptosis, and fibrogenesis, leading to the acceleration of hepatocarcinogenesis in liver-specific Pten mutant mice. Sav1/Pten double-mutant livers also showed a striking up-regulation of markers of liver progenitor cells (LPCs), along with synergistic activation of Yap, which is a major downstream effector of Hippo signaling. Lastly, Yap activation, in combination with Pten inactivation, was found to accelerate cell growth and sphere formation of LPCs in vitro and induce their malignant transformation in allografts. Our forward genetic screens in mice have thus identified pathways and genes driving the development of NAFLD-HCC.
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http://dx.doi.org/10.1073/pnas.1808968115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217425PMC
October 2018

inactivation reveals Hippo function in alveolar type I cell differentiation during lung transition to air breathing.

Development 2018 11 9;145(21). Epub 2018 Nov 9.

Laboratory of Genetics, Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA

Lung growth to its optimal size at birth is driven by reiterative airway branching followed by differentiation and expansion of alveolar cell types. How this elaborate growth is coordinated with the constraint of the chest is poorly understood. Here, we investigate the role of Hippo signaling, a cardinal pathway in organ size control, in mouse lung development. Unexpectedly, we found that epithelial loss of the Hippo kinase genes and () leads to a striking reduction of lung size owing to an early arrest of branching morphogenesis. This growth defect is accompanied by abnormalities in epithelial cell polarity, cell division plane and extracellular matrix deposition, as well as precocious and increased expression of markers for type 1 alveolar epithelial cells (AEC1s), an indicator of terminal differentiation. Increased AEC1s were also observed in transgenic mice with overexpression of a constitutive nuclear form of downstream transcriptional effector YAP. Conversely, loss of and led to decreased AEC1s, demonstrating that the canonical Hippo signaling pathway is both sufficient and necessary to drive AEC1 fate. These findings together reveal unique roles of Hippo-LATS-YAP signaling in the developing mouse lung.
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http://dx.doi.org/10.1242/dev.163105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240317PMC
November 2018

Integrated Genomic Comparison of Mouse Models Reveals Their Clinical Resemblance to Human Liver Cancer.

Mol Cancer Res 2018 11 6;16(11):1713-1723. Epub 2018 Aug 6.

Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Hepatocellular carcinoma (HCC) is a heterogeneous disease. Mouse models are commonly used as preclinical models to study hepatocarcinogenesis, but how well these models recapitulate molecular subtypes of human HCC is unclear. Here, integration of genomic signatures from molecularly and clinically defined human HCC ( = 11) and mouse models of HCC ( = 9) identified the mouse models that best resembled subtypes of human HCC and determined the clinical relevance of each model. knockout (KO), KO, and SV40 T antigen mouse models effectively recapitulated subtypes of human HCC with a poor prognosis, whereas the transgenic model best resembled human HCCs with a more favorable prognosis. The model was also associated with activation of β-catenin. , and diethylnitrosamine (DEN)-induced models were heterogeneous and were unequally split into poor and favorable prognoses. KO and KO models best resemble human HCC with hepatic stem cell characteristics. Applying a genomic predictor for immunotherapy, the six-gene IFNγ score, the KO, KO, SV40, and DEN models were predicted to be the least responsive to immunotherapy. Further analysis showed that elevated expression of immune-inhibitory genes ( and Nectin2/) in KO, KO, and SV40 models and decreased expression of immune stimulatory gene () in the DEN model might be accountable for the lack of predictive response to immunotherapy. The current genomic approach identified the most relevant mouse models to human liver cancer and suggests immunotherapeutic potential for the treatment of specific subtypes. .
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431260PMC
November 2018

Anti-osteogenic function of a LIM-homeodomain transcription factor LMX1B is essential to early patterning of the calvaria.

Dev Biol 2018 11 28;443(2):103-116. Epub 2018 May 28.

Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, United States. Electronic address:

The calvaria (upper part of the skull) is made of plates of bone and fibrous joints (sutures and fontanelles), and the proper balance and organization of these components are crucial to normal development of the calvaria. In a mouse embryo, the calvaria develops from a layer of head mesenchyme that surrounds the brain from shortly after mid-gestation. The mesenchyme just above the eye (supra-orbital mesenchyme, SOM) generates ossification centers for the bones, which then grow toward the apex gradually. In contrast, the mesenchyme apical to SOM (early migrating mesenchyme, EMM), including the area at the vertex, does not generate an ossification center. As a result, the dorsal midline of the head is occupied by sutures and fontanelles at birth. To date, the molecular basis for this regional difference in developmental programs is unknown. The current study provides vital insights into the genetic regulation of calvarial patterning. First, we showed that osteogenic signals were active in both EMM and SOM during normal development, which suggested the presence of an anti-osteogenic factor in EMM to counter the effect of these signals. Subsequently, we identified Lmx1b as an anti-osteogenic gene that was expressed in EMM but not in SOM. Furthermore, head mesenchyme-specific deletion of Lmx1b resulted in heterotopic ossification from EMM at the vertex, and craniosynostosis affecting multiple sutures. Conversely, forced expression of Lmx1b in SOM was sufficient to inhibit osteogenic specification. Therefore, we conclude that Lmx1b plays a key role as an anti-osteogenic factor in patterning the head mesenchyme into areas with different osteogenic competence. In turn, this patterning event is crucial to generating the proper organization of the bones and soft tissue joints of the calvaria.
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http://dx.doi.org/10.1016/j.ydbio.2018.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197925PMC
November 2018

Publisher Correction: The transcriptional coactivator TAZ regulates reciprocal differentiation of T17 cells and T cells.

Nat Immunol 2018 Sep;19(9):1036

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.

In the version of this article initially published, the institution name for affiliation 3 (Maryland Anderson Cancer Center) was incorrect. The correct institution is MD Anderson Cancer Center. The error has been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41590-018-0055-9DOI Listing
September 2018

Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis.

Cancer Cell 2018 02;33(2):292-308.e7

Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China. Electronic address:

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage-derived sarcomas. Molecular events driving SC-to-MPNST transformation are incompletely understood. 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 hyperproliferation. Conversely, disruption of TAZ/YAP activity alleviates tumor burden in Lats1/2-deficient mice and inhibits human MPNST cell proliferation. Moreover, genome-wide profiling reveals that TAZ/YAP-TEAD1 directly activates oncogenic programs, including platelet-derived growth factor receptor (PDGFR) signaling. Co-targeting TAZ/YAP and PDGFR pathways inhibits tumor growth. Thus, our findings establish a previously unrecognized convergence between Lats1/2-TAZ/YAP signaling and MPNST pathogenesis, revealing potential therapeutic targets in these untreatable tumors.
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http://dx.doi.org/10.1016/j.ccell.2018.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813693PMC
February 2018

Hippo pathway coactivators Yap and Taz are required to coordinate mammalian liver regeneration.

Exp Mol Med 2018 01 5;50(1):e423. Epub 2018 Jan 5.

Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

The mammalian liver has a remarkable capacity for repair following injury. Removal of up to two-third of liver mass results in a series of events that include extracellular matrix remodeling, coordinated hepatic cell cycle re-entry, restoration of liver mass and tissue remodeling to return the damaged liver to its normal state. Although there has been considerable advancement of our knowledge concerning the regenerative capacity of the mammalian liver, many outstanding questions remaining, such as: how does the regenerating liver stop proliferating when appropriate mass is restored and how do these mechanisms relate to normal regulation of organ size during development? Hippo pathway has been proposed to be central in mediating both events: organ size control during development and following regeneration. In this report, we examined the role of Yap and Taz, key components of the Hippo pathway in liver organ size regulation, both in the context of development and homeostasis. Our studies reveal that contrary to the current paradigms that Yap/Taz are not required for developmental regulation of liver size but are required for proper liver regeneration. In livers depleted of Yap and Taz, liver mass is elevated in neonates and adults. However, Yap/Taz-depleted livers exhibit profound defects in liver regeneration, including an inability to restore liver mass and to properly coordinate cell cycle entry. Taken together, our results highlight requirements for the Hippo pathway during liver regeneration and indicate that there are additional pathways that cooperate with Hippo signaling to control liver size during development and in the adult.
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http://dx.doi.org/10.1038/emm.2017.205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992983PMC
January 2018
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