A Critical Role for Notch Signaling in the Formation of Cholangiocellular Carcinomas

Zender, Steffen; Nickeleit, Irina; Wüestefeld, Torsten; Sörensen, Inga; Dauch, Daniel; Bożko, Przemysław; El-Khatib, Mona; Geffers, Robert; Bektaş, H.; Manns, Michael P.; Gossler, Achim; Wilkens, Ludwig; Plentz, Ruben R.; Zender, Lars; Malek, Nisar P.

doi:10.1016/j.ccr.2013.04.019

Cited by 177 publications

(166 citation statements)

References 37 publications

(44 reference statements)

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“…Our findings, alternatively, suggest that hepatocytes are the source of this ductular outgrowth. Combined with recent findings (Fan et al, 2012; Sekiya and Suzuki, 2012; Zender et al, 2013), our work argues in favor of a new paradigm in which hepatocytes might be the cell-of-origin not only for cholangiocarcinoma but also for mixed-phenotype liver cancer, typically thought to arise from oval cells.…”

Section: Discussionsupporting

confidence: 71%

Hippo Pathway Activity Influences Liver Cell Fate

Yimlamai

Christodoulou

Galli

et al. 2014

Cell

708

810

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The Hippo signaling pathway is an important regulator of cellular proliferation and organ size. However, little is known about the role of this cascade in the control of cell fate. Employing a combination of lineage tracing, clonal analysis, and organoid culture approaches, we demonstrate that Hippo-pathway activity is essential for the maintenance of the differentiated hepatocyte state. Remarkably, acute inactivation of Hippo-pathway signaling in vivo is sufficient to de-differentiate, at very high efficiencies, adult hepatocytes into cells bearing progenitor characteristics. These hepatocyte-derived progenitor cells demonstrate self-renewal and engraftment capacity at the single cell level. We also identify the NOTCH signaling pathway as a functional important effector downstream of the Hippo transducer YAP. Our findings uncover a potent role for Hippo/YAP signaling in controlling liver cell fate, and reveal an unprecedented level of phenotypic plasticity in mature hepatocytes, which has implications for the understanding and manipulation of liver regeneration.

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Section: Discussionsupporting

confidence: 71%

Hippo Pathway Activity Influences Liver Cell Fate

Yimlamai

Christodoulou

Galli

et al. 2014

Cell

708

810

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“…41 Aberrant notch signalling is also implicated in liver cancer. 42,43 Notch signalling is vital to normal liver development, and has a major role in biliary lineage determination. 44 Comparative functional genomics identified activation of Notch in around 30% of human HCCs, providing the rationale for selective Notch blockade in a subset of patients with HCC.…”

Section: Signalling Pathwaysmentioning

confidence: 99%

Advances in targeted therapies for hepatocellular carcinoma in the genomic era

et al. 2015

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Mortality owing to liver cancer has increased in the past 20 years, and the latest estimates indicate that the global health burden of this disease will continue to grow. Most patients with hepatocellular carcinoma (HCC) are still diagnosed at intermediate or advanced disease stages, where curative approaches are often not feasible. Among the treatment options available, the molecular targeted agent sorafenib is able to significantly increase overall survival in these patients. Thereafter, up to seven large, randomized phase III clinical trials investigating other molecular therapies in the first-line and second-line settings have failed to improve on the results observed with this agent. Potential reasons for this include intertumour heterogeneity, issues with trial design and a lack of predictive biomarkers of response. During the past 5 years, substantial advances in our knowledge of the human genome have provided a comprehensive picture of commonly mutated genes in patients with HCC. This knowledge has not yet influenced clinical decision-making or current clinical practice guidelines. In this Review the authors summarize the molecular concepts of progression, discuss the potential reasons for clinical trial failure and propose new concepts of drug development, which might lead to clinical implementation of emerging targeted agents.

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“…Activation of the Notch pathway in vascular endothelial cells is triggered by norepinephrine-induced Jagged 1 expression in breast cancer cells Accumulating evidence indicates that tumor cell-stromal cell interaction may be influenced by the Jagged/Notch pathway (Zeng et al 2005, Sethi et al 2011, Lu et al 2013, Xing et al 2013, Zender et al 2013. Results from recent studies have indicated that the Notch signaling pathway is directly involved in physiological and pathological angiogenesis (Dufraine et al 2008, Benedito et al 2009).…”

Section: Resultsmentioning

confidence: 99%