Endothelial Notch1 Activity Facilitates Metastasis

Wieland, Elfriede; Rodríguez-Vita, Juan; Liebler, Sven S.; Mogler, Carolin; Moll, Iris; Herberich, Stefanie E.; Espinet, Elisa; Herpel, Esther; Menuchin, Amitai; Chang‐Claude, Jenny; Hoffmeister, Michael; Gebhardt, Christoffer; Brenner, Hermann; Trumpp, Andreas; Siebel, Christian W.; Hecker, Markus; Utikal, Jochen; Sprinzak, David; Fischer, Andreas

doi:10.1016/j.ccell.2017.01.007

Cited by 246 publications

(221 citation statements)

References 69 publications

(94 reference statements)

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“…Another potential application of GSi treatment based on our study is related to the capacity to inhibit metastasis, thus defining GSi as a “migrastatic” drug. Increasing evidence supports a role for NOTCH signaling in metastasis, exemplified by the capacity of NOTCH1 to trigger premetastatic niche formation . In CCA, we observed elevated NOTCH1 to be associated with lymph node metastasis in patients with advanced disease as well as enrichment of metastasis signatures in predicted GSi responders.…”

Section: Discussionsupporting

confidence: 60%

Identification of a Pan‐Gamma‐Secretase Inhibitor Response Signature for Notch‐Driven Cholangiocarcinoma

et al. 2019

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Cholangiocarcinoma (CCA) mortality rates are increasing as a result of rising incidence and limited curative treatment(s) for patients with advanced disease. NOTCH pathway reactivation has been reported in biliary malignancies to conflicting degrees, hindering prioritization of key therapeutic targets within the network and identification of candidate responder patients for NOTCH‐directed therapies. We analyzed genomic data from 341 patients with CCA and identified NOTCH1 significantly increased in a subgroup characterized by distinct stromal infiltration. Network‐wide imbalance of the NOTCH pathway was seen in CCA, including correlation of NOTCH1 with NOTCH3 and NOTCH ligands. Given the diversity of observed NOTCH receptor engagement, γ‐secretase modulation was rationalized as a therapeutic option. Indeed, subcutaneous transplantation of sensitive and resistant CCA cell lines pretreated with a γ‐secretase inhibitor (GSi) cocktail demonstrated the antineoplastic effects of GSi in a subset of CCA and led to the development of a 225‐gene responder signature. This signature was validated in an independent cohort of 119 patients. Further, this signature was enriched in liver tumors initiated by hydrodynamic injections of activated‐NOTCH as compared with the AKT‐RAS‐driven tumors. Candidate GSi‐responder patients were characterized by distinct transcriptomes overlapping with previous hepatobiliary metastasis and stemness, unique stromal properties, and dysfunctional intratumoral immune infiltration. Pan‐cancer analysis identified 41.9% of cancer types to harbor prospective GSi‐responder patients, which was adapted into a 20‐gene GSi‐sensitivity score metric capable of discriminating nanomolar versus micromolar sensitivity to a cell‐permeable GSi (Z‐LLNle‐CHO) across 60 diverse tumor lines (area under the curve = 1). Conclusion: We have established a GSi‐responder signature with evidence across several patient cohorts, as well as in vitro and in vivo models, to enable precision medicine application of NOTCH‐directed therapy in CCA as well as prospectively across diverse malignancies.

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Section: Discussionsupporting

confidence: 60%

Identification of a Pan‐Gamma‐Secretase Inhibitor Response Signature for Notch‐Driven Cholangiocarcinoma

et al. 2019

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“…Moreover, other groups have also demonstrated that the Notch signals in EC are involved in tumor progression and stem cell phenotype . Notch activation in EC promotes tumor cell migration and metastasis along with neutrophil infiltration …”

Section: Role Of Tumor Endothelial Cells In Tumor Progression and Metmentioning

confidence: 98%

Tumor endothelial cells accelerate tumor metastasis

2017

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Tumor metastasis is the main cause of cancer‐related death. Understanding the molecular mechanisms underlying tumor metastasis is crucial to control this fatal disease. Several molecular pathways orchestrate the complex biological cell events during a metastatic cascade. It is now well known that bidirectional interaction between tumor cells and their microenvironment, including tumor stroma, is important for tumor progression and metastasis. Tumor stromal cells, which acquire their specific characteristics in the tumor microenvironment, accelerate tumor malignancy. The formation of new blood vessels, termed as tumor angiogenesis, is a requirement for tumor progression. Tumor blood vessels supply nutrients and oxygen and also provide the route for metastasis. Tumor endothelial cells, which line tumor blood vessels, also exhibit several altered phenotypes compared with those of their normal counterparts. Recent studies have emphasized “angiocrine factors” that are released from tumor endothelial cells and promote tumor progression. During intravasation, tumor cells physically contact tumor endothelial cells and interact with them by juxtacrine and paracrine signaling. Recently, we observed that in highly metastatic tumors, tumor endothelial cells interact with tumor cells by secretion of a small leucine‐rich repeat proteoglycan known as biglycan. Biglycan from tumor endothelial cells stimulates the tumor cells to metastasize. In the present review, we highlight the role of tumor stromal cells, particularly endothelial cells, in the initial steps of tumor metastasis.

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“…Tumors hypoxia usually leads to massive cell necrosis and is not usually associated with tumor invasion or metastasis. Instead, additional microenvironmental cues, such as inflammatory cytokines and growth factors derived from immune cells, mesenchymal cells, senescence, or necrotic cells are required for EMT and subsequent tumor invasion and metastasis . It is unclear how cellular hypoxic responses and microenvironmental cues interact with each other in EMT induction resulting in tumor invasion and metastasis.…”

mentioning

confidence: 99%

Actin cytoskeleton remodeling drives epithelial‐mesenchymal transition for hepatoma invasion and metastasis in mice

et al. 2018

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Simultaneously activation of actin cytoskeleton remodeling by intrinsic (such as KLHL23 down-regulation) or microenvironment cues is crucial for cell-density-dependent and hypoxia-mediated EMT, providing a mechanistic link between large tumor size and invasion/metastasis. Our findings provide a means of developing the prevention and treatment strategies for tumor invasion and metastasis. (Hepatology 2018;67:2226-2243).

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Endothelial Notch1 Activity Facilitates Metastasis

Cited by 246 publications

References 69 publications

Identification of a Pan‐Gamma‐Secretase Inhibitor Response Signature for Notch‐Driven Cholangiocarcinoma

Identification of a Pan‐Gamma‐Secretase Inhibitor Response Signature for Notch‐Driven Cholangiocarcinoma

Tumor endothelial cells accelerate tumor metastasis

Actin cytoskeleton remodeling drives epithelial‐mesenchymal transition for hepatoma invasion and metastasis in mice

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