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Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice

ABSTRACT: Liver tumors activate a regeneration-like genetic program in surrounding liver tissue akin to the regeneration program activated by toxic liver injury. Using genetically engineered mouse models we show that this program is regulated by the Hippo pathway. Our results identify a novel mechanism of non-autonomous tumor suppression where activation of a regeneration-like program in normal cells around liver tumors caused tumor cell death and tumor regression. Strikingly, deleting YAP specifically in peritumoral hepatocytes resulted in hepatocyte death and enhanced tumor growth, while hyperactivating YAP in peritumoral hepatocytes caused the elimination of tumor cells and tumor regression.

ORGANISM(S): Mus musculus

PROVIDER: GSE103788 | GEO | 2019/09/11

REPOSITORIES: GEO

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Regeneration Defects in Livers of Mice With Mutations in Yap and Taz Caused by Bile Duct Disruption and Cholestasis

Project description:Background and aims: The Hippo pathway and its downstream effectors YAP and TAZ (YAP/TAZ) are heralded as important regulators of organ growth and regeneration. However, different studies provided contradictory conclusions about their role during regeneration of different organs ranging from promoting proliferation to inhibiting it. Here, we resolve the function of YAP/TAZ during regeneration of the liver, where Hippo’s role in growth control has been studied most intensely. Methods: We evaluated liver regeneration after CCl4 toxic liver injury in mice with conditional deletion of Yap/Taz in hepatocytes and/or biliary epithelial cells and measured the behavior of different cell types during regeneration by histology, RNA-sequencing and flow cytometry. Results: We found that YAP/TAZ were activated in hepatocytes in response to CCl4 toxic injury. However, their targeted deletion in adult hepatocytes did not noticeably impair liver regeneration. In contrast, Yap/Taz deletion in adult bile ducts caused severe defects and delay in liver regeneration. Mechanistically, we show that Yap/Taz mutant bile ducts degenerated, causing cholestasis which stalled the recruitment of phagocytic macrophages and the removal of cellular corpses from injury sites. Elevated bile acids activated PXR, which was sufficient to recapitulate the phenotype observed in mutant mice. Conclusions: Our data show that YAP/TAZ are practically dispensable in hepatocytes for liver development and regeneration. Rather, YAP/TAZ play an indirect role in liver regeneration by preserving bile duct integrity and securing immune cell recruitment and function.

2020-11-02 | GSE157088 | GEO

Expression data of FFPE peritumoral neocortex tissue

Project description:Epilepsy is a common cause of morbidity affecting approximately one third of patients with primary brain tumors. However, the molecular mechanism underlying the tumor induced epileptogenesis is poorly understood. The alteration in peritumoral microenvironments is believed to play a significant role in inducing epileptogenesis. We hypothesize that the change of gene expression in neighboring astrocytes and neurons may contribute to the increased neuronal excitability and epileptogenesis. Genome-wide gene expression profiling was conducted using Affymetrix HG U133 plus 2.0 arrays and RNAs derived from formalin-fixed paraffin embedded (FFPE) peritumoral cortex tissue slides from 5-paired (seizure vs. non-seizure) low grade brain tumor patients.

2012-12-11 | E-GEOD-32534 | biostudies-arrayexpress

Gene expression profiling of effect of Yap inhibition in a genetically engineered mouse model of hepatocellular carcinoma

Project description:Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC). Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis. We show that YAP functions as a rheostat maintaining metabolic specialization, differentiation and quiescence within the hepatocyte compartment. Importantly, treatment with siRNA-lipid nanoparticles (siRNA-LNPs) targeting YAP restores hepatocyte differentiation and causes pronounced tumor regression in a genetically engineered mouse HCC model (mice with liver-specific Mst1/Mst2 double knockout). Furthermore, YAP targets are enriched in an aggressive human HCC subtype characterized by a proliferative signature and absence of CTNNB1 mutations. Thus, our work reveals Hippo signaling as a key regulator of positional identity of hepatocytes, supports targeting YAP using siRNA-LNPs as a paradigm of differentiation-based therapy, and identifies an HCC subtype potentially responsive to this approach. Mice with liver-specific Mst1/Mst2 double-knockout (Adeno-Cre injected Mst1-/-; Mst2Flox/Flox mice) were monitored for the formation of HCC by ultrasound imaging. Animals were then randomized to be treated by intravenous injection of either siYap-LNPs or siLuciferase-LNPs for a period of 9 days.

2015-03-07 | E-GEOD-65665 | biostudies-arrayexpress

MiRNome profiling of glioblastoma tissues and peritumoral regions

Project description:Glioblastoma multiforme (GBM) is the most common and deadliest primary brain tumor. Its prognosis is inexorably unfavorable, as these tumors drive affected patients to death usually within 15 months after diagnosis (short term survivors, ST), with the only exception of a small fraction of patients (long term survivors, LT) surviving longer than 36 months. Even after the frontline therapeutic approach, including surgical resection followed by chemo- and radiotherapy, the cause of death in most cases is tumor recurrence, which occurs in peritumoral tissues in about 95% of patients. Here, we provide a comprehensive molecular analysis of a set of ST and LT samples derived from frankly tumoral areas (C) and from the peritumoral regions (P) of the same patients. By performing microRNA deep sequencing, we collected data showing that P areas differ from healthy white matter, but share with C samples, a number of microRNAs

2017-03-08 | E-MTAB-3239 | biostudies-arrayexpress

Functional switching of the peritumoral cutaneous Schwann cells in melanoma

Project description:We utilize Plp1-CreERT/Rosa26Stopt-tdTomato mice to purify by flow cytometry the peritumoral skin Schwann cells from melanoma-bearing mice, and compare them to skin Schwann cells from tumor-free mice by RNA-sequencing.

2023-03-21 | GSE208150 | GEO

Gene expression profiling of effect of Yap inhibition in a genetically engineered mouse model of hepatocellular carcinoma

2015-03-07 | GSE65665 | GEO

Expression data of FFPE peritumoral neocortex tissue

2012-12-11 | GSE32534 | GEO

Transcriptome profiling of glioblastoma tissues and peritumoral regions by Serial Analysis of Gene Expression

Project description:In this study, we report a broad analysis of central tumor samples (C), from both Glioblastoma long term survivors (LT) and short term ones (ST), integrated by the same analysis performed on peritumoral areas (P) from the same patients. We provide data from SAGE analysis performed with deep sequencing.

2017-06-29 | E-MTAB-3258 | biostudies-arrayexpress

A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver injury-associated YAP signaling (ATAC-seq)

Project description:Following injury, differentiated epithelial cells can serve as a stem cell-independent source for tissue regeneration by undergoing reprogramming into other cell types. The intrinsic molecular basis underlying plasticity of differentiated cells remains largely unaddressed. Here we show that Arid1a, a key component of the SWI/SNF chromatin remodeling complex, controls liver regeneration and gene expression associated with emergence of injury-induced progenitor-like cells (LPLCs). Hepatocyte-specific Arid1a ablation reduces LPLC gene expression in several models of periportal liver injury and impairs liver regeneration, leading to organ dysfunction. Arid1a establishes a permissive chromatin state at LPLC-enriched genes during homeostasis, suggesting it endows hepatocytes with competence to respond to injury-induced signals. Consistently, Arid1a facilitates binding of YAP, a critical regeneration signaling pathway, to LPLC-enriched genes, and Arid1a deletion prevents their YAP-associated induction following injury. Together, these findings provide a framework for studying the contributions of injury-induced LPLCs to periportal liver regeneration.

2019-07-07 | GSE111499 | GEO

A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver injury-associated YAP signaling (RNA-seq)

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