Ester Bonastre

Institut d'Investigació Biomédica de Bellvitge

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Montse Sánchez‐Céspedes

Josep Carreras Leukaemia Research Institute

ÉB

Élisabeth Brambilla

Université Grenoble Alpes

Ilse Zondervan

MRC Holland (Netherlands)

Sylvie Lantuéjoul

Université Grenoble Alpes

Suvi Savola

MRC Holland (Netherlands)

Enric Condom

Bellvitge University Hospital

David Sidransky

Johns Hopkins University

Eva Pros

Josep Carreras Leukaemia Research Institute

Federica Facchinetti

Fondazione IRCCS Istituto Nazionale dei Tumori

Julián Carretero

Universitat de València

Cooperative Institutions

Institut d'Investigació Biomédica de Bellvitge

Centro de Investigación Biomédica en Red de Cáncer

Universitat de Barcelona

Institut Català d'Oncologia

Bellvitge University Hospital

Spanish National Cancer Research Centre

Instituto de Salud Carlos III

Centro Nacional de Epidemiología

Centro de Investigación del Cáncer

Centre for Biomedical Network Research on Rare Diseases

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Data from PARD3 Inactivation in Lung Squamous Cell Carcinomas Impairs STAT3 and Promotes Malignant Invasion

Ester Bonastre Sara Verdura Ilse Zondervan Federica Facchinetti Sylvie Lantuéjoul

<div>AbstractCorrect apicobasal polarization and intercellular adhesions are essential for the appropriate development of normal epithelia. Here, we investigated the contribution of the cell polarity regulator PARD3 to the development of lung squamous cell carcinomas (LSCC). Tumor-specific PARD3 alterations were found in 8% of LSCCs examined, placing PARD3 among the most common tumor suppressor genes in this malignancy. Most PAR3-mutant proteins exhibited a relative reduction in the ability to mediate formation of tight junctions and actin-based protrusions, bind atypical protein kinase C, activate RAC1, and activate STAT3 at cell confluence. Thus, PARD3 alterations prevented the formation of contacts between neighboring cells and the subsequent downstream signaling. Notably, reconstituting PAR3 activity in vivo reduced tumor-invasive and metastatic properties. Our findings define PARD3 as a recurrently inactivated cell polarity regulator in LSCC that affects tumor aggressiveness and metastasis. Cancer Res; 75(7); 1287–97. ©2015 AACR.</div>

Cell polarity

10.1158/0008-5472.c.6507201

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Supplementary Figures 1 - 8 from PARD3 Inactivation in Lung Squamous Cell Carcinomas Impairs STAT3 and Promotes Malignant Invasion

Ester Bonastre Sara Verdura Ilse Zondervan Federica Facchinetti Sylvie Lantuéjoul

Figure S1. PARD3-inactivation in the H157 lung cancer cell line. Figure S2. Ratio charts of the multiplex ligation-dependent probe amplification (MLPA) depicting a large intragenic deletion (from exon 4 to 23) in one of the LSCCs but not a normal DNA. Figure S3. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) to determine the presence of promoter hypermethylation of PARD3. Figure S4. Relative abundance of the PARD3 transcriptsFigure S5. Western blot showing ectopic and transient expression of the indicated PAR3 proteins in the H157 cell line, immunoblotted with HA or PAR3 antibodies. Figure S6. Immunofluorescence with the anti-PAR3 antibody in the indicated T98G-derived cells, after (Dox+) induction of PAR3 expression with doxycycline (1 ng/µl, 24h). Scale bar, 50 µm. Figure S7. Western blot depicts the endogenous PAR3 protein in the indicated lung cancer cells and the ectopic expression of PAR3 in the H157tr-pD41_R74del cells (dox, 1 ng/µl; 24 h). Figure S8. Immunostaining of PAR3 in lung primary tumors and head and neck squamous cell carcinomas (HNSCCs).

Ectopic expression

10.1158/0008-5472.22406967

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Supplementary Figures S1, S2 and S3 from Genomic and Molecular Screenings Identify Different Mechanisms for Acquired Resistance to MET Inhibitors in Lung Cancer Cells

Pol Giménez‐Xavier Eva Pros Ester Bonastre Sebastián Moran Ana Aza

Supplementary Figure S1. Cell viability and colony formation assays of the indicated cell lines. Supplementary Figure S2. Multidimensional scaling plots Supplementary Figure S3. Cell viability assays and western blots

10.1158/1535-7163.22504324.v1

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Captions from Genomic and Molecular Screenings Identify Different Mechanisms for Acquired Resistance to MET Inhibitors in Lung Cancer Cells

Pol Giménez‐Xavier Eva Pros Ester Bonastre Sebastián Moran Ana Aza

Captions for supplementary Figures and Tables

10.1158/1535-7163.22504327.v1

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'Supplementary Methods' from Genomic and Molecular Screenings Identify Different Mechanisms for Acquired Resistance to MET Inhibitors in Lung Cancer Cells

Pol Giménez‐Xavier Eva Pros Ester Bonastre Sebastián Moran Ana Aza

'Supplementary Methods'

10.1158/1535-7163.22504333

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Supplementary Figures S1, S2 and S3 from Genomic and Molecular Screenings Identify Different Mechanisms for Acquired Resistance to MET Inhibitors in Lung Cancer Cells

Pol Giménez‐Xavier Eva Pros Ester Bonastre Sebastián Moran Ana Aza

10.1158/1535-7163.22504324

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Abstract 3940: Inactivation of the PARD3 gene is a recurrent event in lung squamous cell carcinomas and affects STAT3 activity and tumor invasiveness

Cancer Research (2015)

Ester Bonastre Sara Verdura Ilse Zondervan Federica Facchinetti Sylvie Lantuéjoul

Abstract Correct apicobasal polarization and intercellular adhesions are essential for the appropriate development of normal epithelia. Here, we investigated the contribution of the partitioning defective 3 gene, PARD3, to the carcinogenesis of lung squamous cell carcinomas (LSCCs). Tumor-specific PARD3 alterations were found in eight per cent of the tumors, placing PARD3 among the most common tumor suppressor genes in LSCC. Some PAR3 mutant proteins prevented the formation of contacts between neighboring cells, i.e. had reduced ability to form tight junctions and actin-based protrusions. This affected subsequent downstream signaling, i.e. binding to aPKC and activation of RAC1. Further, we discovered that PAR3 wild type triggered the expression of cell adhesion and polarity-related transcripts and the activation of STAT3, by cell confluence. Finally, restitution of PAR3 in vivo significantly reduced the formation of metastasis. In conclusion, PARD3 is recurrently inactivated in LSCC and its deficiency contributes to the tumor aggressiveness. Citation Format: Ester Bonastre, Sara Verdura, Ilse Zondervan, Federica Facchinetti, Sylvie Lantuejoul, Maria Dolores Chiara, Juan Pablo Rodrigo, Julian Carretero, David Sidransky, Alberto Villanueva, Enric Condom, Agustin Vidal, Luca Roz, Elisabeth Brambilla, Suvi Savola, Montse Sanchez-Cespedes. Inactivation of the PARD3 gene is a recurrent event in lung squamous cell carcinomas and affects STAT3 activity and tumor invasiveness. [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 3940. doi:10.1158/1538-7445.AM2015-3940

10.1158/1538-7445.am2015-3940

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Supplementary Methods from PARD3 Inactivation in Lung Squamous Cell Carcinomas Impairs STAT3 and Promotes Malignant Invasion

Ester Bonastre Sara Verdura Ilse Zondervan Federica Facchinetti Sylvie Lantuéjoul

Supplementary Materials and Methods

10.1158/0008-5472.22406964

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PARD3 Inactivation in Lung Squamous Cell Carcinomas Impairs STAT3 and Promotes Malignant Invasion

Cancer Research (2015)

Ester Bonastre Sara Verdura Ilse Zondervan Federica Facchinetti Sylvie Lantuéjoul

Correct apicobasal polarization and intercellular adhesions are essential for the appropriate development of normal epithelia. Here, we investigated the contribution of the cell polarity regulator PARD3 to the development of lung squamous cell carcinomas (LSCC). Tumor-specific PARD3 alterations were found in 8% of LSCCs examined, placing PARD3 among the most common tumor suppressor genes in this malignancy. Most PAR3-mutant proteins exhibited a relative reduction in the ability to mediate formation of tight junctions and actin-based protrusions, bind atypical protein kinase C, activate RAC1, and activate STAT3 at cell confluence. Thus, PARD3 alterations prevented the formation of contacts between neighboring cells and the subsequent downstream signaling. Notably, reconstituting PAR3 activity in vivo reduced tumor-invasive and metastatic properties. Our findings define PARD3 as a recurrently inactivated cell polarity regulator in LSCC that affects tumor aggressiveness and metastasis.

Cell polarity

10.1158/0008-5472.can-14-2444

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'Supplementary Tables' from Genomic and Molecular Screenings Identify Different Mechanisms for Acquired Resistance to MET Inhibitors in Lung Cancer Cells

Pol Giménez‐Xavier Eva Pros Ester Bonastre Sebastián Moran Ana Aza

TABLE S1. Sequences used for primers and for the shRNAs. TABLE S2. List of genes selected from the WES, RNA-seq and microarray methylation analysis

10.1158/1535-7163.22504330.v1

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