Regeneration Defects in Yap and Taz Mutant Mouse Livers Are Caused by Bile Duct Disruption and Cholestasis

Verboven, Elisabeth; Moya, Iván M.; Sansores-García, Leticia; Xie, Jun; Hillen, Hanne; Kowalczyk, Weronika; Vella, Gerlanda; Verhulst, Stefaan; Castaldo, Stéphanie A.; Algueró-Nadal, Ana; Romanelli, Lucia; Mercader-Celma, Cristina; Souza, Natália A.; Soheily, Soheil; Huffel, Leen Van; Brussel, Thomas Van; Lambrechts, Diether; Roskams, Tania; Lemaigre, Frédéric P.; Bergers, Gabrielle; Grunsven, Leo A. van; Halder, Georg

doi:10.1053/j.gastro.2020.10.035

Cited by 45 publications

(56 citation statements)

References 51 publications

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“…Since published results and our first experimental data illustrated a positive impact of YAP expression on macrophage recruitment, 25 we studied the abundance and spatial localization of macrophages in wt and YAP S127A transgenic mice. Immunofluorescence (IF) stains for two macrophage markers (CD11b and F4/80) followed by semi‐automated image segmentation allowed the quantification of changes in the macrophage compartment.…”

Section: Resultsmentioning

confidence: 99%

YAP‐induced Ccl2 expression is associated with a switch in hepatic macrophage identity and vascular remodelling in liver cancer

Thomann

Weiler

Teng

et al. 2021

Liver International

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Section: Resultsmentioning

confidence: 99%

YAP‐induced Ccl2 expression is associated with a switch in hepatic macrophage identity and vascular remodelling in liver cancer

Thomann

Weiler

Teng

et al. 2021

Liver International

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“…Although this body of evidence suggests that simultaneous TAZ and YAP inhibition might help restrain the growth of human iCCA, previous findings indicate that concomitant loss of the two genes severely impairs liver regeneration and paradoxically drives the development of hepatocellular adenomas [ 49 , 50 ]. Thus, treatment approaches targeting TAZ and YAP should be cautiously evaluated in preclinical models before being applied to the clinical setting.…”

Section: Discussionmentioning

confidence: 99%

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

Cigliano

Zhang

Ribback

et al. 2022

J Exp Clin Cancer Res

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Background Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive primary liver tumor with increasing incidence worldwide, dismal prognosis, and few therapeutic options. Mounting evidence underlines the role of the Hippo pathway in this disease; however, the molecular mechanisms whereby the Hippo cascade contributes to cholangiocarcinogenesis remain poorly defined. Methods We established novel iCCA mouse models via hydrodynamic transfection of an activated form of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo pathway downstream effector, either alone or combined with the myristoylated AKT (myr-AKT) protooncogene, in the mouse liver. Hematoxylin and eosin staining, immunohistochemistry, electron microscopy, and quantitative real-time RT-PCR were applied to characterize the models. In addition, in vitro cell line studies were conducted to address the growth-promoting roles of TAZ and its paralog YAP. Results Overexpression of TAZ in the mouse liver triggered iCCA development with very low incidence and long latency. In contrast, co-expression of TAZ and myr-AKT dramatically increased tumor frequency and accelerated cancer formation in mice, with 100% iCCA incidence and high tumor burden by 10 weeks post hydrodynamic injection. AKT/TAZ tumors faithfully recapitulated many of the histomolecular features of human iCCA. At the molecular level, the development of the cholangiocellular lesions depended on the binding of TAZ to TEAD transcription factors. In addition, inhibition of the Notch pathway did not hamper carcinogenesis but suppressed the cholangiocellular phenotype of AKT/TAZ tumors. Also, knockdown of YAP, the TAZ paralog, delayed cholangiocarcinogenesis in AKT/TAZ mice without affecting the tumor phenotype. Furthermore, human preinvasive and invasive iCCAs and mixed hepatocellular carcinoma/iCCA displayed widespread TAZ activation and downregulation of the mechanisms protecting TAZ from proteolysis. Conclusions Overall, the present data underscore the crucial role of TAZ in cholangiocarcinogenesis

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“…No clinically available therapeutic agents exist and impaired/dysfunctional liver regeneration continues to carry a high degree of morbidity and mortality especially in the post-hepatectomy setting (6,7). Preclinical studies have demonstrated a central role for YAP in regulating liver regeneration, however, the exact mechanisms both upstream and downstream of YAP remain unresolved and contradictory (17,23,(50)(51)(52). For example, TGF-β has been suggested to be both required for YAP-mediated regenerative signaling and detrimental (39,52).…”

Section: Discussionmentioning

confidence: 99%

SHP2 inhibition enhances Yes-associated protein–mediated liver regeneration in murine partial hepatectomy models

Watkins¹,

Buckarma²,

Tomlinson³

et al. 2022

JCI Insight

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Disrupted liver regeneration following hepatectomy represents an "undruggable" clinical challenge associated with poor patient outcomes. Yes-associated protein (YAP), a transcriptional co-activator which is repressed by the Hippo pathway, is instrumental in liver regeneration. We have previously described an alternative, Hippo-independent, mechanism of YAP activation mediated by tyrosine-protein phosphatase non-receptor type 11 (SHP2) inhibition. Herein, we examined the effects of YAP activation with a selective SHP1/SHP2 inhibitor, NSC-87877, on liver regeneration in murine partial hepatectomy models. In our studies, NSC-87877 led to accelerated hepatocyte proliferation, improved liver regeneration, and decreased markers of injury following partial hepatectomy. The effects of NSC-87877 were lost in mice with hepatocytespecific Yap/Taz deletion, which demonstrated dependence on these molecules for the enhanced regenerative response. Furthermore, administration of NSC-87877 to murine models of nonalcoholic steatohepatitis was associated with improved survival and decreased markers of injury post-hepatectomy. Evaluation of transcriptomic changes in the context of NSC-87877 administration revealed reduction in fibrotic signaling and augmentation of cell cycle signaling.Cytoprotective changes included downregulation of Nr4a1, an apoptosis inducer. Collectively, the data suggest that SHP2 inhibition induces a pro-proliferative and cytoprotective enhancement of liver regeneration dependent on YAP.

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Regeneration Defects in Yap and Taz Mutant Mouse Livers Are Caused by Bile Duct Disruption and Cholestasis

Cited by 45 publications

References 51 publications

YAP‐induced Ccl2 expression is associated with a switch in hepatic macrophage identity and vascular remodelling in liver cancer

YAP‐induced Ccl2 expression is associated with a switch in hepatic macrophage identity and vascular remodelling in liver cancer

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

SHP2 inhibition enhances Yes-associated protein–mediated liver regeneration in murine partial hepatectomy models

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