Road to perdition: Zeb1-dependent and –independent ways to metastasis

Brabletz, Simone; Brabletz, Thomas; Stemmler, Marc P.

doi:10.1080/15384101.2017.1360648

Cited by 5 publications

(2 citation statements)

References 7 publications

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“…Therefore, additional preclinical work to explore the molecular processes underlying these disease outcomes is necessary, and the antibodies presented here will aid in such endeavors. In particular, because tumor cells with “hybrid” or “partial” EMT phenotypes may be the true drivers of drug resistance and metastasis in some cancers [ 1 – 4 ], and given the temporal and spatial heterogeneity of EMT and CSC protein expression patterns in different histological contexts [ 3 , 38 – 43 ], examination of multiple EMT and CSC factors within each tissue specimen may be necessary to fully understand the molecular basis of drug-resistant and metastatic tumor phenotypes. Our novel anti-EMT TF and anti-CSC antibodies are well-suited for IFA analysis of tumor tissue, and multiplex assays using several of these antibodies simultaneously will allow for careful dissection of the role of each target protein in preclinical specimens.…”

Section: Discussionmentioning

confidence: 99%

Novel antibody reagents for characterization of drug- and tumor microenvironment-induced changes in epithelial-mesenchymal transition and cancer stem cells

Navas¹,

Pfister²,

Colantonio³

et al. 2018

PLoS ONE

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The presence of cancer stem cells (CSCs) and the induction of epithelial-to-mesenchymal transition (EMT) in tumors are associated with tumor aggressiveness, metastasis, drug resistance, and poor prognosis, necessitating the development of reagents for unambiguous detection of CSC- and EMT-associated proteins in tumor specimens. To this end, we generated novel antibodies to EMT- and CSC-associated proteins, including Goosecoid, Sox9, Slug, Snail, and CD133. Importantly, unlike several widely used antibodies to CD133, the anti-CD133 antibodies we generated recognize epitopes distal to known glycosylation sites, enabling analyses that are not confounded by differences in CD133 glycosylation. For all target proteins, we selected antibodies that yielded the expected target protein molecular weights by Western analysis and the correct subcellular localization patterns by immunofluorescence microscopy assay (IFA); binding selectivity was verified by immunoprecipitation−mass spectrometry and by immunohistochemistry and IFA peptide blocking experiments. Finally, we applied these reagents to assess modulation of the respective markers of EMT and CSCs in xenograft tumor models by IFA. We observed that the constitutive presence of human hepatocyte growth factor (hHGF) in the tumor microenvironment of H596 non-small cell lung cancer tumors implanted in homozygous hHGF knock-in transgenic mice induced a more mesenchymal-like tumor state (relative to the epithelial-like state when implanted in control SCID mice), as evidenced by the elevated expression of EMT-associated transcription factors detected by our novel antibodies. Similarly, our new anti-CD133 antibody enabled detection and quantitation of drug-induced reductions in CD133-positive tumor cells following treatment of SUM149PT triple-negative breast cancer xenograft models with the CSC/focal adhesion kinase (FAK) inhibitor VS-6063. Thus, our novel antibodies to CSC- and EMT-associated factors exhibit sufficient sensitivity and selectivity for immunofluorescence microscopy studies of these processes in preclinical xenograft tumor specimens and the potential for application with clinical samples.

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Section: Discussionmentioning

confidence: 99%

Novel antibody reagents for characterization of drug- and tumor microenvironment-induced changes in epithelial-mesenchymal transition and cancer stem cells

Navas¹,

Pfister²,

Colantonio³

et al. 2018

PLoS ONE

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“…This study highlighted a clear role for cytokines from the stromal compartment in inducing EMP in certain PDAC cell lines, and indicated that EMP activation could be observed in discrete tumour gland subunits with prognostic utility. These models have provided considerable insights into the diverse mechanisms of PDAC development, and highlight that there are context-dependent EMP programs involved in both local invasion and metastatic dissemination that require further examination [72,78].…”

Section: Emp and Pdac Progressionmentioning

confidence: 99%

Targeting Epithelial Mesenchymal Plasticity in Pancreatic Cancer: A Compendium of Preclinical Discovery in a Heterogeneous Disease

Monkman

Thompson

Nagaraj

2019

Cancers

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Pancreatic Ductal Adenocarcinoma (PDAC) is a particularly insidious and aggressive disease that causes significant mortality worldwide. The direct correlation between PDAC incidence, disease progression, and mortality highlights the critical need to understand the mechanisms by which PDAC cells rapidly progress to drive metastatic disease in order to identify actionable vulnerabilities. One such proposed vulnerability is epithelial mesenchymal plasticity (EMP), a process whereby neoplastic epithelial cells delaminate from their neighbours, either collectively or individually, allowing for their subsequent invasion into host tissue. This disruption of tissue homeostasis, particularly in PDAC, further promotes cellular transformation by inducing inflammatory interactions with the stromal compartment, which in turn contributes to intratumoural heterogeneity. This review describes the role of EMP in PDAC, and the preclinical target discovery that has been conducted to identify the molecular regulators and effectors of this EMP program. While inhibition of individual targets may provide therapeutic insights, a single ‘master-key’ remains elusive, making their collective interactions of greater importance in controlling the behaviours’ of heterogeneous tumour cell populations. Much work has been undertaken to understand key transcriptional programs that drive EMP in certain contexts, however, a collaborative appreciation for the subtle, context-dependent programs governing EMP regulation is needed in order to design therapeutic strategies to curb PDAC mortality.

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Bittersweet tumor development and progression: Emerging roles of epithelial plasticity glycosylations

Phillips

Wang

et al. 2019

Advances in Cancer Research

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Road to perdition: Zeb1-dependent and –independent ways to metastasis

Cited by 5 publications

References 7 publications

Novel antibody reagents for characterization of drug- and tumor microenvironment-induced changes in epithelial-mesenchymal transition and cancer stem cells

Novel antibody reagents for characterization of drug- and tumor microenvironment-induced changes in epithelial-mesenchymal transition and cancer stem cells

Targeting Epithelial Mesenchymal Plasticity in Pancreatic Cancer: A Compendium of Preclinical Discovery in a Heterogeneous Disease

Bittersweet tumor development and progression: Emerging roles of epithelial plasticity glycosylations

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