<i>Sox9</i> mediates Notch1-induced mesenchymal features in lung adenocarcinoma

Capaccione, Kathleen M.; Hong, Xuehui; Morgan, Katherine M.; Liu, Wenyu; Bishop, Michael J.; Liu, Lianxin; Markert, Elke; Deen, Malik; Minerowicz, Christine; Allen, T. C.; Pine, Sharon R.

doi:10.18632/oncotarget.1970

Cited by 69 publications

(69 citation statements)

References 48 publications

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“…As expected, BMS-906024 generally decreased levels of activated Notch1 ICD, as well as the Notch1 target gene SOX9 (22), in the tumors (Fig. 6A).…”

Section: Resultssupporting

confidence: 81%

“…Cells were cultured as described (22), used in experiments within 2 months after thawing, and were authenticated in January 2017 by short tandem repeat (STR) profiling at the Rutgers New Jersey Medical School Molecular Resource Facility (Newark, NJ), using the GenePrint 24 System (Promega). Data were interpreted as described (23).…”

Section: Methodsmentioning

confidence: 99%

“…cDNA was synthesized using the QuantiTect Reverse Transcription Kit (Qiagen). qRT-PCR was conducted using Power SYBR Green PCR Master Mix (Applied Biosystems) on a Stratagene Mx3005p qPCR system (Agilent Technologies) (22). Reactions were done in triplicate.…”

Section: Methodsmentioning

confidence: 99%

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Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma

Morgan

Fischer

Lee

et al. 2017

Molecular Cancer Therapeutics

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Notch signaling is aberrantly activated in approximately one third of non-small cell lung cancers (NSCLC). We characterized the interaction between BMS-906024, a clinically relevant Notch gamma secretase inhibitor (GSI), and front-line chemotherapy in preclinical models of NSCLC. Chemosensitivity assays were performed on 14 human NSCLC cell lines. There was significantly greater synergy between BMS-906024 and paclitaxel than BMS-906024 and cisplatin (mean CI value = 0.54 and 0.85, respectively, P = 0.01). On an extended panel of 31 NSCLC cell lines, 25 of which were adenocarcinoma, the synergy between BMS-906024 and paclitaxel was significantly greater in KRAS- and BRAF-wildtype than KRAS- or BRAF-mutant cells (mean CI = 0.43 vs. 0.90, respectively; P = 0.003). Paclitaxel-induced Notch1 activation was associated with synergy between BMS-906024 and paclitaxel in the KRAS- or BRAF-mutant group. Knockdown of mutant KRAS increased the synergy between BMS-906024 and paclitaxel in heterozygous KRAS-mutant cell lines. Among KRAS- or BRAF-mutant NSCLC, there was a significant correlation between synergy and mutant or null TP53 status, as well as between synergy and a low H2O2 pathway signature. Exogenous overexpression of activated Notch1 or Notch3 had no effect on the enhanced sensitivity of NSCLC to paclitaxel by BMS-906024. In vivo studies with cell line- and patient-derived lung adenocarcinoma xenografts confirmed enhanced antitumor activity for BMS-906024 plus paclitaxel versus either drug alone via decreased cell proliferation and increased apoptosis. These results show that BMS-906024 sensitizes NSCLC to paclitaxel, and that wildtype KRAS and BRAF status may predict better patient response to the combination therapy.

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“…As expected, BMS-906024 generally decreased levels of activated Notch1 ICD, as well as the Notch1 target gene SOX9 (22), in the tumors (Fig. 6A).…”

Section: Resultssupporting

confidence: 81%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma

Morgan

Fischer

Lee

et al. 2017

Molecular Cancer Therapeutics

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“…Since Sox9 has been described as a Notch1 mediator in EMT activation in lung adenocarcinoma [106], it could play a similar role in CCA.…”

Section: Development-related Pathways (Figure 2d)mentioning

confidence: 99%

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

124

122

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Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis due to its late clinical presentation and the lack of effective non-surgical therapies. Unfortunately, most of the patients are not eligible for curative surgery owing to the presence of metastases at the time of diagnosis. Therefore, it is important to understand the steps leading to cell dissemination in patients with CCA. To metastasize from the primary site, cancer cells must acquire migratory and invasive properties by a cell plasticity-promoting phenomenon known as epithelial-mesenchymal transition (EMT). EMT is a reversible dynamic process by which epithelial cells gradually adopt structural and functional characteristics of mesenchymal cells, and has lately become a center of attention in the field of metastatic dissemination. In the present review, we aim to provide an extensive overview of the current clinical data and the prognostic value of different EMT markers that have been analyzed in CCA. We summarize all the regulatory networks implicated in EMT from the membrane receptors to the main EMT-inducing transcription factors (SNAIL, TWIST and ZEB). Furthermore, since a tumor is a complex structure not exclusively formed by tumor cells, we also address the prominent role of the main cell types of the desmoplastic stroma that characterizes CCA in the regulation of EMT. Finally, we discuss the therapeutic considerations and difficulties faced to develop an effective anti-EMT treatment due to the redundancies and bypasses among the pathways regulating EMT. 4Key Point Box -EMT is an early event of metastasis that endows tumor cells with invasive properties enabling them to spread toward other territories.-EMT contributes to CCA progression and chemoresistance.-The three families of transcription factors that regulate epithelial and mesenchymal marker expression during EMT (SNAIL, TWIST and ZEB) contribute to CCA progression.-Cells of CCA microenvironment, and not only cancer cells, lead to the activation of EMT.

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“…Some of them, including downregulated Id2, Sim2, Maf2 and Atoh8 or upregulated Sox9 transcription factors, could be involved in regulating specific sets of EMT-associated genes. 48,49 Our data show that the expression of Snail1, as well as E-cadherin and vimentin markers, change significantly upon depletion of lnc-Spy1. Ectopic expression of the transcriptional repressor Snail1 50 did not affect the expression level of lnc-Spry1, indicating that lnc-Spry1 could function upstream or independently of the Snail1 signaling pathway.…”

Section: Discussionmentioning

confidence: 70%

Downregulation of Lnc-Spry1 mediates TGF-β-induced epithelial–mesenchymal transition by transcriptional and posttranscriptional regulatory mechanisms

et al. 2017

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Long non-coding RNAs (lncRNAs) are a class of regulatory genes that participate in a wide range of biological processes, including proliferation, differentiation and development, as well as in a broad spectrum of diseases. Although the role of lncRNAs in TGF-β-induced epithelial-to-mesenchymal transition (EMT) has been well established, little is known about the role of lncRNAs as immediate-early regulators of EMT. Here lnc-Spry1 is identified as an immediate-early regulator of EMT that is downregulated by TGF-β. It is also found that knockdown of lnc-Spry1 promotes a mesenchymal-like phenotype and results in increased cell migration and invasion. In addition, it is shown that lnc-Spry1 depletion preferentially affects the expression of TGF-β-regulated gene targets. Moreover, lnc-Spry1 associates with U2AF65 splicing factor, suggesting a role in alternative splicing. Depletion of lnc-Spry1 induces, as TGF-β, isoform switching of fibroblast growth factor receptors, resulting in FGF-2-sensitive cells. Taken together, these results show that lnc-Spry1 could act as an early mediator of TGF-β signaling and reveal different roles for a lncRNA in modulating transcriptional and posttranscriptional gene expression. Cell Death and Differentiation (2017) 24, 785-797; doi:10.1038/cdd.2017.9; published online 10 February 2017EMT is a basic cellular process in which epithelial cells lose their epithelial characteristics and take on properties of mesenchymal cells. During EMT, epithelial cells lose their cell-cell junctions and the epithelial apical-basal polarity. The actin cytoskeleton is reorganized and cells acquire migratory and invasive properties.1-3 This process is essential in the generation of tissues and organs during embryogenesis, during wound healing and is associated with pathologies, such as fibrosis and cancer. In carcinomas, cancer cells can undergo EMT to escape the primary tumor, invade surrounding tissues and colonize remote sites via blood or lymphatic routes generating metastases. 4-6The EMT program can be activated efficiently and rapidly in epithelial cells in response to soluble factors or cytokines, including epidermal growth factor, fibroblast growth factors (FGFs) and transforming growth factors (TGF-βs). TGF-β may induce EMT through distinct signaling mechanisms causing substantial changes in gene expression. These changes involve three families of transcription factors: the zinc finger Snail, Zeb, and basic helix-loop-helix families. 7Beyond the well-established transcriptional reprogramming during EMT, posttranscriptional mechanisms, such as regulation by alternative pre-mRNA splicing and regulation by noncoding RNA, have an important role and provide an additional layer of complexity on the gene regulation during EMT. 8-12The mammalian genome encodes many thousands of lncRNAs, a class of transcripts 4200 nucleotides with limited protein-coding potential.13 They can act as molecular signals, tethers, decoys, guides or scaffolds at every level of gene regulation in a wide range of biological proc...

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Sox9 mediates Notch1-induced mesenchymal features in lung adenocarcinoma

Cited by 69 publications

References 48 publications

Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma

Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Downregulation of Lnc-Spry1 mediates TGF-β-induced epithelial–mesenchymal transition by transcriptional and posttranscriptional regulatory mechanisms

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