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  • 1
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    Abstract 4098: Musashi-2 (MSI2) activates TGF-β signaling and inhibits CLDN7 to promote non-small cell lung cancer (NSCLC) metastasis
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4098-4098
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4098-4098
    Abstract: Approximately 220,000 new patients were diagnosed with lung cancer and ∼160,000 died from this disease in the United States in 2014. Non-small cell lung cancer (NSCLC) has a 5 year survival rate of approximately 16%, with most deaths associated with distant metastasis. To gain a better insight into the regulation of metastasis, we studied metastasis-competent versus low metastasis-potential cell lines derived from NSCLC tumors of KrasLA1/+; P53R172HG/+ (KP) mice. Initial screening showed consistent and statistically significant upregulation of Musashi-2 (MSI2) in highly metastatic cells on both mRNA and protein level. Furthermore, we established statistically significant elevation of MSI2 protein expression in 123 human NSCLC tumor specimens versus normal lung tissue (p & lt;0.0001). MSI2 is an RNA binding protein that regulates mRNA translation and is upregulated and functionally important in hematologic malignancies including CML and AML. MSI2 knockdown in four independent metastatic murine and human NSCLC cell lines very significantly decreased invasion in vitro but did not significantly change cell proliferation or survival. In orthotropic lung injection of mouse NSCLC cells into the lungs of immunocompetent 129Sv mice, MSI2 depletion dramatically decreased invasion of mediastinal lymph nodes and abrogated metastasis. Reverse-phase protein array (RPPA) screening indicated that Msi2 depletion significantly affected the expression of multiple proteins associated with epithelial-mesenchymal transition (EMT) and control of cell-cell attachments, including the extracellular matrix component fibronectin (FN1) and the tight junction protein claudin-7 (CLDN7). These and additional targets were validated in all four NSCLC model systems. MSI2 dependent control of FN1 expression was mediated at the level of mRNA induction, while CLDN7 expression was strikingly upregulated (10-fold) at the protein but not mRNA level, nominating CLDN7 as a putative direct MSI2 target. Parallel evaluation of a series of candidate direct MSI2 translational targets indicated MSI2 depletion downregulated translation of TGF-β receptor (TGF-βRI) and SMAD3. Morphologically, MSI2 depleted cells were marked by a greater degree of cell-cell attachment, potentially explaining their decreased invasive capacity. Based on this work, we propose that MSI2 supports TGF-βRI dependent EMT signaling and downregulates tight junction controls in a subset of metastatic NSCLC, and may influence tumor response to inhibitors targeting the TGF-β pathway. Citation Format: Alexander Kudinov, Alexander Deneka Deneka, Anna Nikonova, Young-Ho Ahn, Xin Liu Liu, Ilya Serebriiskii, Andrey Efimov, Dong-Hua Yang, Mark Andrake Andrake, Emmanuelle Nicolas, Brian Egleston, Hossein Borghaei, Don Gibbons, Jonathan Kurie, Erica Golemis, Yanis Boumber. Musashi-2 (MSI2) activates TGF-β signaling and inhibits CLDN7 to promote non-small cell lung cancer (NSCLC) metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4098. doi:10.1158/1538-7445.AM2015-4098
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-4098
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 2
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    Abstract 4452: Musashi-2 regulates EGFR/HER3 expression in NSCLC, cell proliferation and response to EGFR inhibitors in EGFR-mutant NSCLC
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 4452-4452
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 4452-4452
    Abstract: Musashi-2 (MSI2) is an RNA-binding protein that regulates mRNA translation. We recently established that MSI2 is elevated in a subset of non-small cell lung cancer (NSCLC) tumors upon progression and drives NSCLC metastasis, in part based on activity supporting a TGF-beta/SMAD3/claudin signaling cascade. Here, reverse phase protein array (RPPA) analysis of MSI2-depleted versus control KrasLA1/+;P53R172HΔG/+ murine NSCLC cell lines identified a significant ~2.7-fold upregulation of HER3 (ERBB3) upon MSI2 depletion. Negative MSI2-dependent regulation of ERBB3 protein was confirmed in multiple NSCLC models, based on analysis of MSI2 depletion or overexpression. Further, MSI2 positively regulated expression of the epidermal growth factor receptor (EGFR) protein in the same models. Comparing EGFR and KRAS driven models, we found that MSI2 depletion significantly impairs cell proliferation only in EGFR-mutant NSCLC cell lines. Using RNA immunoprecipitation analysis coupled with qPCR, we show that MSI2 directly binds to EGFR and, to a lesser extent, to HER3 mRNA. MSI2 mRNA binding was approximately correlating with the presence of predicted MSI2 binding sites in corresponding mRNAs. NSCLC lung tissue microarray analysis revealed that MSI2 total positivity by H-score, 2+/3+ and 3+ positivity correlated with EGFR 3+ staining. Finally, EGFR inhibitors erlotinib and afatinib synergized with MSI2 depletion in EGFR mutant models, suggesting that therapeutic targeting of MSI2 could be of clinical value, especially in EGFR-mutant lung cancer. Citation Format: Peter Makhov, Alexander Kudinov, Alexander Deneka, Brian L. Egleston, Emmanuelle Nicolas, Kathy Q. Cai, Rohan Brebion, Eleanor Avril, Mark Hitrik, Anna S. Nikonova, Ilya G. Serebriiskii, Vladimir Khazak, Hossein Borghaei, Erica A. Golemis, Yanis Boumber. Musashi-2 regulates EGFR/HER3 expression in NSCLC, cell proliferation and response to EGFR inhibitors in EGFR-mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4452.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-4452
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 3
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    A Novel HSP90 Inhibitor–Drug Conjugate to SN38 Is Highly Effective in Small Cell Lung Cancer
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 20 ( 2016-10-15), p. 5120-5129
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 20 ( 2016-10-15), p. 5120-5129
    Abstract: Purpose: Small cell lung cancer (SCLC) is a highly aggressive disease representing 12% to 13% of total lung cancers, with median survival of & lt;2 years. No targeted therapies have proven effective in SCLC. Although most patients respond initially to cytotoxic chemotherapies, resistance rapidly emerges, response to second-line agents is limited, and dose-limiting toxicities (DLT) are a major issue. This study performs preclinical evaluation of a new compound, STA-8666, in SCLC. Experimental Design: To avoid DLT for useful cytotoxic agents, the recently developed drug STA-8666 combines a chemical moiety targeting active HSP90 (concentrated in tumors) fused via cleavable linker to SN38, the active metabolite of irinotecan. We compare potency and mechanism of action of STA-8666 and irinotecan in vitro and in vivo. Results: In two SCLC xenograft and patient-derived xenograft models, STA-8666 was tolerated without side effects up to 150 mg/kg. At this dose, STA-8666 controlled or eliminated established tumors whether used in a first-line setting or in tumors that had progressed following treatment on standard first- and second-line agents for SCLC. At 50 mg/kg, STA-8666 strongly enhanced the action of carboplatin. Pharmacokinetic profiling confirmed durable STA-8666 exposure in tumors compared with irinotecan. STA-8666 induced a more rapid, robust, and stable induction of cell-cycle arrest, expression of signaling proteins associated with DNA damage and cell-cycle checkpoints, and apoptosis in vitro and in vivo, in comparison with irinotecan. Conclusions: Together, these results strongly support clinical development of STA-8666 for use in the first- or second-line setting for SCLC. Clin Cancer Res; 22(20); 5120–9. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-15-3068
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 4
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    Abstract 3878: Musashi-2 (MSI2) regulation of ERBB family proteins in non-small cell lung cancer (NSCLC)
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3878-3878
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3878-3878
    Abstract: The purpose of this study is to establish whether a new signaling axis we recently described can be targeted to improve patient survival in lung cancer, one of the leading causes of death worldwide, with over 1.6 million deaths annually. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. A small number of targeted therapies have been shown to be useful in lung cancer, including inhibitors of EGFR, but these are typically only active in a subset of tumors that maintain epithelial characteristics. Musashi-2 (MSI2), an RNA-binding protein that regulates mRNA translation, has been linked to maintenance of a stem cell state in multiple hematologic and solid tumor malignancies. We recently established (Kudinov et al, PNAS 2016, PMID:27274057) that MSI2 is elevated in a subset of NSCLC tumor upon progression and drives NSCLC metastasis, in part based on activity supporting a TGF-beta/SMAD3/claudin signaling cascade that enhances epithelial-mesenchymal transition (EMT). Using reverse phase protein array (RPPA) analysis of MSI2-depleted versus control KrasLA1/+;P53R172HΔG/+ murine NSCLC cell line models identified a significant 2.7-fold upregulation of HER3 upon MSI2 depletion. Negative MSI2-dependent regulation of ERBB3 protein expression was confirmed in multiple additional murine and human KRAS-dependent NSCLC models, based on analysis of MSI2 depletion or overexpression. In contrast, MSI2 positively regulated expression of the EGFR/ERBB1 protein in the same models. In detailed analysis, we have addressed the mechanism by which MSI2 regulates expression of the ERBB group of receptor tyrosine kinases. In addition, these data suggested the hypothesis that MSI2 expression might predict response to EGFR-targeted inhibitors, and that dual targeting of MSI2 and EGFR might be therapeutically valuable. We will present data on the activity of EGFR inhibitors in the context of depleted or elevated MSI2 expression, and the effect of combining inhibition of EGFR with recently developed MSI2 inhibitors. In summary, these results for the first time indicate a role of MSI2 in supporting EGFR expression in NSCLC and suggest that MSI2 may drive NSCLC development and progression in part via EGFR, and may modulate response to EGFR-targeted agents. Citation Format: Alexander Kudinov, Alexander Deneka, Anna N. Nikonova, Emmanuelle Nicolas, Vladislav A. Korobeynikov, Ilya G. Serebriiskii, John Karanicolas, Erica A. Golemis, Yanis Boumber. Musashi-2 (MSI2) regulation of ERBB family proteins in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3878. doi:10.1158/1538-7445.AM2017-3878
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-3878
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 5
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    15. Mainzer Allergie-Workshop 2003 : Frühjahrstagung der Deutschen Gesellschaft für Allergologie und klinische Immunologie am 14. und 15. März 2003
    Springer Science and Business Media LLC ; 2003
    In:  Allergo Journal Vol. 12, No. 1 ( 2003-2), p. 36-56
    Details
    In: Allergo Journal, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2003-2), p. 36-56
    Type of Medium: Online Resource
    ISSN: 0941-8849 , 2195-6405
    URL: Article
    DOI: 10.1007/BF03361093
    Language: German
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2003
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  • 6
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    Musashi-2 (MSI2) regulates epidermal growth factor receptor (EGFR) expression and response to EGFR inhibitors in EGFR-mutated non-small cell lung cancer (NSCLC)
    Springer Science and Business Media LLC ; 2021
    In:  Oncogenesis Vol. 10, No. 3 ( 2021-03-15)
    Details
    In: Oncogenesis, Springer Science and Business Media LLC, Vol. 10, No. 3 ( 2021-03-15)
    Abstract: Non-small cell lung cancer (NSCLC) has limited treatment options. Expression of the RNA-binding protein (RBP) Musashi-2 (MSI2) is elevated in a subset of non-small cell lung cancer (NSCLC) tumors upon progression, and drives NSCLC metastasis. We evaluated the mechanism of MSI2 action in NSCLC to gain therapeutically useful insights. Reverse phase protein array (RPPA) analysis of MSI2-depleted versus control Kras LA1/+ ; Trp53 R172HΔG/+ NSCLC cell lines identified EGFR as a MSI2-regulated protein. MSI2 control of EGFR expression and activity in an NSCLC cell line panel was studied using RT-PCR, Western blots, and RNA immunoprecipitation. Functional consequences of MSI2 depletion were explored for cell growth and response to EGFR-targeting drugs, in vitro and in vivo. Expression relationships were validated using human tissue microarrays. MSI2 depletion significantly reduced EGFR protein expression, phosphorylation, or both. Comparison of protein and mRNA expression indicated a post-transcriptional activity of MSI2 in control of steady state levels of EGFR. RNA immunoprecipitation analysis demonstrated that MSI2 directly binds to EGFR mRNA, and sequence analysis predicted MSI2 binding sites in the murine and human EGFR mRNAs. MSI2 depletion selectively impaired cell proliferation in NSCLC cell lines with activating mutations of EGFR (EGFR mut ). Further, depletion of MSI2 in combination with EGFR inhibitors such as erlotinib, afatinib, and osimertinib selectively reduced the growth of EGFR mut NSCLC cells and xenografts. EGFR and MSI2 were significantly co-expressed in EGFR mut human NSCLCs. These results define MSI2 as a direct regulator of EGFR protein expression, and suggest inhibition of MSI2 could be of clinical value in EGFR mut NSCLC.
    Type of Medium: Online Resource
    ISSN: 2157-9024
    URL: Article
    DOI: 10.1038/s41389-021-00317-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 7
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    Preclinical efficacy of STA-12-8666, an HSP90 inhibitor-targeted SN-38 conjugate, in small cell lung cancer (SCLC).
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 15_suppl ( 2015-05-20), p. e18560-e18560
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. e18560-e18560
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2015.33.15_suppl.e18560
    RVK:
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    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
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  • 8
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    Abstract 874: MSI2 regulates VEGFR2 signaling and tumor progression in NSCLC
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 874-874
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 874-874
    Abstract: Lung cancer holds second place in incidence and first place in mortality among all cancers, both in men and women, with metastasis contributing to the vast majority of deaths. Recently, expression of vascular endothelial growth factor receptor-2 (VEGFR2) on both endothelial and tumor cells was demonstrated as one of the key mechanisms contributing to growth of non-small cell lung cancer (NSCLC), the most common subtype of lung cancer. VEGFR2 dependent signaling is critical both for tumor autocrine functions related to NSCLC migration, and in paracrine control of tumor angiogenesis through action on tumor-proximal endothelial cells, suggesting a potential mechanism for growth control. Several drugs targeting VEGFR2 signaling pathway demonstrated their clinical efficacy in NSCLC setting, including VEGFR2 and VEGF-A inhibitors, VEGF-A/PIGF trap. Recently our group demonstrated that RNA-binding protein Musashi-2 (MSI2) is driving progression and metastasis of NSCLC. MSI2 regulates mRNA translation of multiple targets, its expression is upregulated in the metastasis-competent murine and human lung cancer cell lines and is progressively elevated in lung cancer samples. The goal of this study is to define the role of MSI2 in sustaining VEGFR2 signaling during NSCLC progression. Using reverse RNA immunoprecipitation (RIP) qPCR analysis, we demonstrate that MSI2 directly binds VEGFR2 mRNA. Reverse protein phase array (RPPA) of several NSCLC cell line models with expression or knockdown of MSI2 and subsequent direct validation showed that MSI2 strongly and positively regulates expression of VEGFR2. Subsequent mechanistical analysis revealed that MSI2 knockdown leads to decreased VEGFR2 protein and mRNA levels expression in several NSCLC cell lines in vitro, resulting in increased apoptosis via inhibition of VEGFR2 signaling pathway. To better characterize MSI2 biology, we’ve crossed the B6/129S4-Msi2tm1.1Cjl/J (M2) mice with B6/129S/Sv-Krastm3Tyj/J;Trp53tm1Brn/J (KP) mice and generated novel B6/129S/Sv-KP;Msi2-/- (KPM2) mouse model. Induction of tumorigenesis in KP mice using Cre adenovirus leads to development of lung adenocarcinoma. Induction of lung-specific Cre resulted in tumorigenesis in both KP and KPM2 mice. Interestingly, we observed significant decrease in both total lung tumor number and total lung tumor burden in KPM2 compared to KP mice. Next, we established three novel KP and KPM2 derived cell lines from mouse lung tumors and found that KPM2 cell lines demonstrate reduced proliferation capacity and VEGFR2 mRNA level relative to KP cell lines. Additional studies to understand an impact of MSI2 deletion in KP cell lines are ongoing. Taken together, MSI2 is a promising target for NSCLC treatment, as this protein regulates VEGFR2 signaling and apoptosis in cell models and contributes to KP tumorigenesis in vivo. Citation Format: Igor Bychkov, Alexander Deneka, Iuliia Topchu, Petr Makhov, Alexander Kudinov, Anna Nikonova, John Karanicolas, Erica Golemis, Christopher Lengner, Hossein Borghaei, Jyoti Patel, Yanis Boumber. MSI2 regulates VEGFR2 signaling and tumor progression in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 874.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-874
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 9
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    Abstract 955: Musashi-2 regulates EGFR expression in NSCLC, cell proliferation and survival, response to EGFR inhibitors in EGFR-mutant NSCLC
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 955-955
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 955-955
    Abstract: Musashi-2 (MSI2) is an RNA-binding protein that regulates mRNA translation. We recently established that MSI2 is elevated in a subset of non-small cell lung cancer (NSCLC) tumors upon progression and drives NSCLC metastasis, in part based on activity supporting a TGF-beta/SMAD3/claudin signaling cascade. Here, reverse phase protein array (RPPA) analysis of MSI2-depleted versus control KrasLA1/+;P53R172HΔG/+ murine NSCLC cell lines identified a significant upregulation of HER3 (ERBB3) upon MSI2 depletion. Negative MSI2-dependent regulation of ERBB3 protein was confirmed in multiple murine and human NSCLC models, based on analysis of MSI2 depletion or overexpression. Further, MSI2 positively regulated expression of the epidermal growth factor receptor (EGFR) protein in the same models. Comparing EGFR and KRAS driven models, we found that MSI2 depletion significantly impairs cell proliferation and clonogenicity only in EGFR-mutant NSCLC cell lines. Using RNA immunoprecipitation analysis coupled with qPCR, we show that MSI2 directly binds to EGFR and, to a lesser extent, to HER3 mRNA. MSI2 mRNA binding was correlating with the presence of predicted MSI2 binding sites in corresponding mRNAs. Taken together, this data suggest direct regulation of EGFR protein expression by MSI2 at post transcriptional level. NSCLC lung tissue microarray immunohistochemistry analysis revealed that MSI2 total positivity by H-score, 2+/3+ and 3+ positivity correlated with EGFR 3+ staining. Finally, EGFR inhibitors erlotinib and afatinib synergized with MSI2 depletion in EGFR mutant models, suggesting that therapeutic targeting of MSI2 could be of clinical value, especially in EGFR-mutant lung cancer. In vivo experiments of erlotinib treatments of wild type or MSI2 depleted tumors are ongoing and these results will be presented. Citation Format: Alexander Kudinov, Petr Makhov, Bulat Faezov, Igor Bychkov, Alexander Deneka, Emmanuelle Nicolas, Kathy Q Q. Caid, Rohan Brebione, Eleanor Avrilf, Anna S. Nikonova, Ilya G. Serebriiskii, Hossein Borghaei, Erica A. Golemis, Yanis Boumber. Musashi-2 regulates EGFR expression in NSCLC, cell proliferation and survival, response to EGFR inhibitors in EGFR-mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 955.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-955
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 10
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    Abstract 1584: Musashi-2 (MSI2) drives TGFBR1/SMAD3 dependent partial EMT and supports VEGFR2 expression and metastasis of human and mouse NSCLC cells
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1584-1584
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1584-1584
    Abstract: About 221,200 new patients will be diagnosed with lung cancer and ∼158,040 will succumb to this disease in the United States in 2015. Non-small cell lung cancer (NSCLC) has a 17.4% overall 5-year survival, with metastasis contributing to the vast majority of deaths. Analyzing NSCLC tumors spontaneously arising in KrasLA1/+; P53R172HG/+ (KP) mice, we identified Musashi-2 (MSI2) protein, a stem cell-associated factor that is regulates mRNA translation, as upregulated in the metastasis-competent mouse cell lines. Importantly, MSI2 shRNA depletion in either mouse or human NSCLC cells decreased invasion in Matrigel in vitro and decreased metastasis upon orthotopic injection 129Sv immunocompetent mice in vivo. Mechanistically, by both overexpressing Msi2 cDNA in 393p murine NSCLC and shRNA depleting MSI2 in four independent mouse and human NSCLC cell lines, we defined MSI2 as a driver of a partial epithelial-mesenchymal transition (EMT) program in NSCLC cells. In support of EMT, MSI2 increases the expression of the Snail and Slug pro-EMT transcription factors, as well as the mesenchymal protein vimentin (VMN). MSI2 also downregulates expression of the extracellular matrix component fibronectin (FN1) and tight junction proteins Claudin-3, 5 and 7. However, MSI2 also inhibits protein expression of Zeb-1 and Zeb-2, while sustaining expression of E-cadherin (E-Cad), associated with epithelial identity. Moreover, MSI2 represses NOTCH-1 and upregulates VEGFR2 at the mRNA and protein levels. This is of interest, as NOTCH-1 has been shown to regulate VEGFR2 in angiogenic signaling. We found that knockdown of NOTCH-1 in MSI2-depleted mouse and human NSCLC cells rescued the loss of VEGFR2 expression, suggesting MSI2 increases VEGFR2 expression in a NOTCH-1 dependent manner. Additionally, siRNA of VEGFR2 in the highly metastatic NSCLC cell line 344sq significantly decreased Matrigel invasion, but had only a limited effect in 344sq derivative lines with stable depletion of MSI2, and human NSCLC experiments are ongoing. Together, these results indicate a possible role of MSI2/NOTCH-1/VEGFR2 axis in NSCLC, and suggest that MSI2 connects cancer cell stemness, EMT, and angiogenesis in lung cancer metastasis. Citation Format: Alexander Kudinov, Alexander Deneka, Anna Nikonova, Ilya Serebriiskii, Tim N. Beck, Qi Cai, Brian L. Egleston, Emmanuelle Nicolas, Hossein Borghaei, Don Gibbons, Jonathan Kurie, Erica A. Golemis, Yanis Boumber. Musashi-2 (MSI2) drives TGFBR1/SMAD3 dependent partial EMT and supports VEGFR2 expression and metastasis of human and mouse NSCLC cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1584.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-1584
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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