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2. 3-Dimensional mesothelioma spheroids provide closer to natural pathophysiological tumor microenvironment for drug response studies

Author

Shi, Huaikai, primary, Rath, Emma M., additional, Lin, Ruby C. Y., additional, Sarun, Kadir Harun, additional, Clarke, Candice Julie, additional, McCaughan, Brian C., additional, Ke, Helen, additional, Linton, Anthony, additional, Lee, Kenneth, additional, Klebe, Sonja, additional, Maitz, Joanneke, additional, Song, Kedong, additional, Wang, Yiwei, additional, Kao, Steven, additional, and Cheng, Yuen Yee, additional

Published
2022
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5. The Role of E-Cadherin and microRNA on FAK Inhibitor Response in Malignant Pleural Mesothelioma (MPM)

Author

Yuen, Man Lee, primary, Zhuang, Ling, additional, Rath, Emma M., additional, Yu, Takun, additional, Johnson, Ben, additional, Sarun, Kadir Harun, additional, Wang, Yiwei, additional, Kao, Steven, additional, Linton, Anthony, additional, Clarke, Candice Julie, additional, McCaughan, Brian C., additional, Takahashi, Ken, additional, Lee, Kenneth, additional, and Cheng, Yuen Yee, additional

Published
2021
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10. 3-Dimensional mesothelioma spheroids provide closer to natural pathophysiological tumor microenvironment for drug response studies.

Author

Huaikai Shi, Rath, Emma M., Lin, Ruby C. Y., Sarun, Kadir Harun, Clarke, Candice Julie, McCaughan, Brian C., Ke, Helen, Linton, Anthony, Lee, Kenneth, Klebe, Sonja, Maitz, Joanneke, Kedong Song, Yiwei Wang, Kao, Steven, and Yuen Yee Cheng

Subjects
TUMOR microenvironment, XENOGRAFTS, MESOTHELIOMA, CELL culture, CELL junctions, TRANSVERSE electromagnetic cells
Abstract

Traditional studies using cancer cell lines are often performed on a twodimensional (2D) cell culture model with a low success rate of translating to Phase I or Phase II clinical studies. In comparison, with the advent of developments three-dimensional (3D) cell culture has been championed as the latest cellular model system that better mimics in vivo conditions and pathological conditions such as cancer. In comparison to biospecimens taken from in vivo tissue, the details of gene expression of 3D culture models are largely undefined, especially in mesothelioma - an aggressive cancer with very limited effective treatment options. In this study, we examined the veracity of the 3D mesothelioma cell culture model to study cell-to-cell interaction, gene expression and drug response from 3D cell culture, and compared them to 2D cell and tumor samples. We confirmed via SEM analysis that 3D cells grown using the spheroid methods expressed highly interconnected cell-to-cell junctions. The 3D spheroids were revealed to be an improved mini-tumor model as indicated by the TEM visualization of cell junctions and microvilli, features not seen in the 2D models. Growing 3D cell models using decellularized lung scaffold provided a platform for cell growth and infiltration for all cell types including primary cell lines. The most time-effective method was growing cells in spheroids using low-adhesive U-bottom plates. However, not every cell type grew into a 3D model using the the other methods of hanging drop or poly-HEMA. Cells grown in 3D showed more resistance to chemotherapeutic drugs, exhibiting reduced apoptosis. 3D cells stained with H&E showed cell-to-cell interactions and internal architecture that better represent that of in vivo patient tumors when compared to 2D cells. IHC staining revealed increased protein expression in 3D spheroids compared to 2D culture. Lastly, cells grown in 3D showed very different microRNA expression when compared to that of 2D counterparts. In conclusion, 3D cell models, regardless of which method is used. Showed a more realistic tumor microenvironment for architecture, gene expression and drug response, when compared to 2D cell models, and thus are superior preclinical cancer models. [ABSTRACT FROM AUTHOR]

Published
2022
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11. Dysregulated Expression of the MicroRNA miR-137 and Its Target YBX1 Contribute to the Invasive Characteristics of Malignant Pleural Mesothelioma

Author

Johnson, Thomas G, Schelch, Karin, Cheng, Yuen Y, Williams, Marissa, Sarun, Kadir H, Kirschner, Michaela B, Kao, Steven, Linton, Anthony, Klebe, Sonja, McCaughan, Brian C, Lin, Ruby C Y, Pirker, Christine, Berger, Walter, Lasham, Annette, van Zandwijk, Nico, Reid, Glen, Johnson, Thomas G, Schelch, Karin, Cheng, Yuen Y, Williams, Marissa, Sarun, Kadir H, Kirschner, Michaela B, Kao, Steven, Linton, Anthony, Klebe, Sonja, McCaughan, Brian C, Lin, Ruby C Y, Pirker, Christine, Berger, Walter, Lasham, Annette, van Zandwijk, Nico, and Reid, Glen

Abstract

INTRODUCTION Malignant pleural mesothelioma (MPM) is an aggressive malignancy linked to asbestos exposure. On a genomic level, MPM is characterized by frequent chromosomal deletions of tumor suppressors, including microRNAs. MiR-137 plays a tumor suppressor role in other cancers, so the aim of this study was to characterize it and its target Y-box binding protein 1 (YBX1) in MPM. METHODS Expression, methylation, and copy number status of miR-137 and its host gene MIR137HG were assessed by polymerase chain reaction. Luciferase reporter assays confirmed a direct interaction between miR-137 and Y-box binding protein 1 gene (YBX1). Cells were transfected with a miR-137 inhibitor, miR-137 mimic, and/or YBX1 small interfering RNA, and growth, colony formation, migration and invasion assays were conducted. RESULTS MiR-137 expression varied among MPM cell lines and tissue specimens, which was associated with copy number variation and promoter hypermethylation. High miR-137 expression was linked to poor patient survival. The miR-137 inhibitor did not affect target levels or growth, but interestingly, it increased miR-137 levels by means of mimic transfection suppressed growth, migration, and invasion, which was linked to direct YBX1 downregulation. YBX1 was overexpressed in MPM cell lines and inversely correlated with miR-137. RNA interference-mediated YBX1 knockdown significantly reduced cell growth, migration, and invasion. CONCLUSIONS MiR-137 can exhibit a tumor-suppressive function in MPM by targeting YBX1. YBX1 knockdown significantly reduces tumor growth, migration, and invasion of MPM cells. Therefore, YBX1 represents a potential target for novel MPM treatment strategies.

Published
2018

20. CDKN2A and MTAP Are Useful Biomarkers Detectable by Droplet Digital PCR in Malignant Pleural Mesothelioma: A Potential Alternative Method in Diagnosis Compared to Fluorescence In Situ Hybridisation

Author

Cheng, Yuen Yee, primary, Yuen, Man Lee, additional, Rath, Emma M., additional, Johnson, Ben, additional, Zhuang, Ling, additional, Yu, Ta-kun, additional, Aleksova, Vesna, additional, Linton, Anthony, additional, Kao, Steven, additional, Clarke, Candice Julie, additional, McCaughan, Brian C., additional, Takahashi, Ken, additional, and Lee, Kenneth, additional

Published
2020
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25. KCa1.1, a calcium-activated potassium channel subunit alpha 1, is targeted by miR-17-5p and modulates cell migration in malignant pleural mesothelioma

Author

Cheng, Yuen Yee, Wright, Casey M, Kirschner, Michaela B, Williams, Marissa, Sarun, Kadir H, Sytnyk, Vladimir, Leshchynska, Iryna, Edelman, J James, Vallely, Michael P, McCaughan, Brian C, Klebe, Sonja, van Zandwijk, Nico, Lin, Ruby C Y, Reid, Glen, Cheng, Yuen Yee, Wright, Casey M, Kirschner, Michaela B, Williams, Marissa, Sarun, Kadir H, Sytnyk, Vladimir, Leshchynska, Iryna, Edelman, J James, Vallely, Michael P, McCaughan, Brian C, Klebe, Sonja, van Zandwijk, Nico, Lin, Ruby C Y, and Reid, Glen

Abstract

BACKGROUND Malignant pleural mesothelioma (MPM) is an aggressive, locally invasive, cancer elicited by asbestos exposure and almost invariably a fatal diagnosis. To date, we are one of the leading laboratory that compared microRNA expression profiles in MPM and normal mesothelium samples in order to identify dysregulated microRNAs with functional roles in mesothelioma. We interrogated a significant collection of MPM tumors and normal pleural samples in our biobank in search for novel therapeutic targets. METHODS Utilizing mRNA-microRNA correlations based on differential gene expression using Gene Set Enrichment Analysis (GSEA), we systematically combined publicly available gene expression datasets with our own MPM data in order to identify candidate targets for MPM therapy. RESULTS We identified enrichment of target binding sites for the miR-17 and miR-30 families in both MPM tumors and cell lines. RT-qPCR revealed that members of both families were significantly downregulated in MPM tumors and cell lines. Interestingly, lower expression of miR-17-5p (P = 0.022) and miR-20a-5p (P = 0.026) was clearly associated with epithelioid histology. We interrogated the predicted targets of these differentially expressed microRNA families in MPM cell lines, and identified KCa1.1, a calcium-activated potassium channel subunit alpha 1 encoded by the KCNMA1 gene, as a target of miR-17-5p. KCa1.1 was overexpressed in MPM cells compared to the (normal) mesothelial line MeT-5A, and was also upregulated in patient tumor samples compared to normal mesothelium. Transfection of MPM cells with a miR-17-5p mimic or KCNMA1-specific siRNAs reduced mRNA expression of KCa1.1 and inhibited MPM cell migration. Similarly, treatment with paxilline, a small molecule inhibitor of KCa1.1, resulted in suppression of MPM cell migration. CONCLUSION These functional data implicating KCa1.1 in MPM cell migration support our integrative approach using MPM gene expression datasets to identify novel and pote

Published
2016

26. The IASLC mesothelioma staging project: proposals for the m descriptors and for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for mesothelioma

Author

Rusch, Valerie W, Chansky, Kari, Kindler, Hedy L, Nowak, Anna K, Pass, Harvey I, Rice, David C, Shemanski, Lynn, Galateau-Sallé, Françoise, McCaughan, Brian C, Nakano, Takashi, Ruffini, Enrico, van Meerbeeck, Jan P, Yoshimura, Masahiro, University of Zurich, and Rusch, Valerie W

Subjects
10255 Clinic for Thoracic Surgery, 2740 Pulmonary and Respiratory Medicine, 610 Medicine & health, 2730 Oncology
Published
2016

28. The IASLC Mesothelioma Staging Project: Proposals for the M Descriptors and for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Mesothelioma

Author

Rusch, Valerie W., primary, Chansky, Kari, additional, Kindler, Hedy L., additional, Nowak, Anna K., additional, Pass, Harvey I., additional, Rice, David C., additional, Shemanski, Lynn, additional, Galateau-Sallé, Françoise, additional, McCaughan, Brian C., additional, Nakano, Takashi, additional, Ruffini, Enrico, additional, van Meerbeeck, Jan P., additional, Yoshimura, Masahiro, additional, Goldstraw, Peter, additional, Rami-Porta, Ramón, additional, Asamura, Hisao, additional, Ball, David, additional, Beer, David, additional, Beyruti, Ricardo, additional, Bolejack, Vanessa, additional, Crowley, John, additional, Detterbeck, Frank C., additional, Eberhardt, Wilfried Ernst Erich, additional, Edwards, John, additional, Giroux, Dorothy, additional, Gleeson, Fergus, additional, Groome, Patti, additional, Huang, James, additional, Kennedy, Catherine, additional, Kim, Jhingook, additional, Kim, Young Tae, additional, Kingsbury, Laura, additional, Kondo, Haruhiko, additional, Krasnik, Mark, additional, Kubota, Kaoru, additional, Lerut, Toni, additional, Lyons, Gustavo, additional, Marino, Mirella, additional, Marom, Edith M., additional, Mitchell, Alan, additional, Nicholson, Andrew G., additional, Nowak, Anna, additional, Peake, Michael, additional, Rice, Thomas W., additional, Rosenzweig, Kenneth, additional, Rusch, Valerie W., additional, Saijo, Nagahiro, additional, Van Schil, Paul, additional, Sculier, Jean-Paul, additional, Stratton, Kelly, additional, Suzuki, Kenji, additional, Tachimori, Yuji, additional, Thomas, Charles F., additional, Travis, William D., additional, Tsao, Ming S., additional, Turrisi, Andrew, additional, Vansteenkiste, Johan, additional, Watanabe, Hirokazu, additional, Wu, Yi-Long, additional, Baas, Paul, additional, Erasmus, Jeremy, additional, Hasegawa, Seiki, additional, Inai, Kouki, additional, Kernstine, Kemp, additional, Kindler, Hedy, additional, Krug, Lee, additional, Nackaerts, Kristiaan, additional, Pass, Harvey, additional, Rice, David, additional, Falkson, Conrad, additional, Filosso, Pier Luigi, additional, Giaccone, Giuseppe, additional, Kondo, Kazuya, additional, Lucchi, Marco, additional, Okumura, Meinoshin, additional, Blackstone, Eugene, additional, Asamura, H., additional, Batirel, H., additional, Bille, A., additional, Pastorino, U., additional, Call, S., additional, Cangir, A., additional, Cedres, S., additional, Friedberg, J., additional, Galateau-Sallé, F., additional, Hasagawa, S., additional, Kernstine, K., additional, Kindler, H., additional, McCaughan, B., additional, Nakano, T., additional, Nowak, A., additional, Ozturk, C. Atinkaya, additional, Pass, H., additional, de Perrot, M., additional, Rea, F., additional, Rice, D., additional, Rintoul, R., additional, Ruffini, E., additional, Rusch, V., additional, Spaggiari, L., additional, Galetta, D., additional, Syrigos, K., additional, Thomas, C., additional, van Meerbeeck, J.P., additional, Nafteux, P., additional, Vansteenkiste, J., additional, Weder, W., additional, Optiz, I., additional, and Yoshimura, M., additional

Published
2016
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29. The IASLC Mesothelioma Staging Project: Proposals for the M Descriptors and for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Mesothelioma

Author

Rusch, Valerie W., Chansky, Kari, Kindler, Hedy L., Nowak, Anna K., Pass, Harvey I., Rice, David C., Shemanski, Lynn, Galateau-Sallé, Françoise, McCaughan, Brian C., Nakano, Takashi, Ruffini, Enrico, van Meerbeeck, Jan P., Yoshimura, Masahiro, Goldstraw, Peter, Rami-Porta, Ramón, Asamura, Hisao, Ball, David, Beer, David, Beyruti, Ricardo, Bolejack, Vanessa, Chansky, Kari, Crowley, John, Detterbeck, Frank C., Eberhardt, Wilfried Ernst Erich, Edwards, John, Galateau-Sallé, Françoise, Giroux, Dorothy, Gleeson, Fergus, Groome, Patti, Huang, James, Kennedy, Catherine, Kim, Jhingook, Kim, Young Tae, Kingsbury, Laura, Kondo, Haruhiko, Krasnik, Mark, Kubota, Kaoru, Lerut, Toni, Lyons, Gustavo, Marino, Mirella, Marom, Edith M., van Meerbeeck, Jan P., Mitchell, Alan, Nakano, Takashi, Nicholson, Andrew G., Nowak, Anna, Peake, Michael, Rice, Thomas W., Rosenzweig, Kenneth, Ruffini, Enrico, Rusch, Valerie W., Saijo, Nagahiro, Van Schil, Paul, Sculier, Jean-Paul, Shemanski, Lynn, Stratton, Kelly, Suzuki, Kenji, Tachimori, Yuji, Thomas, Charles F., Travis, William D., Tsao, Ming S., Turrisi, Andrew, Vansteenkiste, Johan, Watanabe, Hirokazu, Wu, Yi-Long, Baas, Paul, Erasmus, Jeremy, Hasegawa, Seiki, Inai, Kouki, Kernstine, Kemp, Kindler, Hedy, Krug, Lee, Nackaerts, Kristiaan, Pass, Harvey, Rice, David, Falkson, Conrad, Filosso, Pier Luigi, Giaccone, Giuseppe, Kondo, Kazuya, Lucchi, Marco, Okumura, Meinoshin, Blackstone, Eugene, Asamura, H., Batirel, H., Bille, A., Pastorino, U., Caja, S. Call, Cangir, A., Cedres, S., Friedberg, J., Galateau-Sallé, F., Hasagawa, S., Kernstine, K., Kindler, H., McCaughan, B., Nakano, T., Nowak, A., Ozturk, C. Atinkaya, Pass, H., de Perrot, M., Rea, F., Rice, D., Rintoul, R., Ruffini, E., Rusch, V., Spaggiari, L., Galetta, D., Syrigos, K., Thomas, C., van Meerbeeck, J.P., Nafteux, P., Vansteenkiste, J., Weder, W., Optiz, I., and Yoshimura, M.

Abstract

The M component and TNM stage groupings for malignant pleural mesothelioma (MPM) have been empirical. The International Association for the Study of Lung Cancer developed a multinational database to propose evidence-based revisions for the eighth edition of the TNM classification of MPM.

Published
2024
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30. KCa1.1, a calcium-activated potassium channel subunit alpha 1, is targeted by miR-17-5p and modulates cell migration in malignant pleural mesothelioma

Author

Cheng, Yuen Yee, primary, Wright, Casey M., additional, Kirschner, Michaela B., additional, Williams, Marissa, additional, Sarun, Kadir H., additional, Sytnyk, Vladimir, additional, Leshchynska, Iryna, additional, Edelman, J. James, additional, Vallely, Michael P., additional, McCaughan, Brian C., additional, Klebe, Sonja, additional, van Zandwijk, Nico, additional, Lin, Ruby C. Y., additional, and Reid, Glen, additional

Published
2016
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32. PD-L1 expression is a favorable prognostic factor in early stage non-small cell carcinoma

Author

Cooper, Wendy A., primary, Tran, Thang, additional, Vilain, Ricardo E., additional, Madore, Jason, additional, Selinger, Christina I., additional, Kohonen-Corish, Maija, additional, Yip, PoYee, additional, Yu, Bing, additional, O’Toole, Sandra A., additional, McCaughan, Brian C., additional, Yearley, Jennifer H., additional, Horvath, Lisa G., additional, Kao, Steven, additional, Boyer, Michael, additional, and Scolyer, Richard A., additional

Published
2015
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33. miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma

Author

Williams, Marissa, primary, Kirschner, Michaela B., additional, Cheng, Yuen Yee, additional, Hanh, Jacky, additional, Weiss, Jocelyn, additional, Mugridge, Nancy, additional, Wright, Casey M., additional, Linton, Anthony, additional, Kao, Steven C., additional, Edelman, J. James B., additional, Vallely, Michael P., additional, McCaughan, Brian C., additional, Cooper, Wendy, additional, Klebe, Sonja, additional, Lin, Ruby C.Y., additional, Brahmbhatt, Himanshu, additional, MacDiarmid, Jennifer, additional, van Zandwijk, Nico, additional, and Reid, Glen, additional

Published
2015
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38. KCa1.1, a calcium-activated potassium channel subunit alpha 1, is targeted by miR-17-5p and modulates cell migration in malignant pleural mesothelioma.

Author

Yuen Yee Cheng, Wright, Casey M., Kirschner, Michaela B., Williams, Marissa, Sarun, Kadir H., Sytnyk, Vladimir, Leshchynska, Iryna, Edelman, J. James, Vallely, Michael P., McCaughan, Brian C., Klebe, Sonja, van Zandwijk, Nico, Lin, Ruby C. Y., and Reid, Glen

Subjects
CALCIUM-dependent potassium channels, CELL migration, MESOTHELIOMA, MICRORNA, MESOTHELIUM, GENE expression
Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive, locally invasive, cancer elicited by asbestos exposure and almost invariably a fatal diagnosis. To date, we are one of the leading laboratory that compared microRNA expression profiles in MPM and normal mesothelium samples in order to identify dysregulated microRNAs with functional roles in mesothelioma. We interrogated a significant collection of MPM tumors and normal pleural samples in our biobank in search for novel therapeutic targets. Methods: Utilizing mRNA-microRNA correlations based on differential gene expression using Gene Set Enrichment Analysis (GSEA), we systematically combined publicly available gene expression datasets with our own MPM data in order to identify candidate targets for MPM therapy. Results: We identified enrichment of target binding sites for the miR-17 and miR-30 families in both MPM tumors and cell lines. RT-qPCR revealed that members of both families were significantly downregulated in MPM tumors and cell lines. Interestingly, lower expression of miR-17-5p (P = 0.022) and miR-20a-5p (P = 0.026) was clearly associated with epithelioid histology. We interrogated the predicted targets of these differentially expressed microRNA families in MPM cell lines, and identified KCa1.1, a calcium-activated potassium channel subunit alpha 1 encoded by the KCNMA1 gene, as a target of miR-17-5p. KCa1.1 was overexpressed in MPM cells compared to the (normal) mesothelial line MeT-5A, and was also upregulated in patient tumor samples compared to normal mesothelium. Transfection of MPM cells with a miR-17-5p mimic or KCNMA1-specific siRNAs reduced mRNA expression of KCa1.1 and inhibited MPM cell migration. Similarly, treatment with paxilline, a small molecule inhibitor of KCa1.1, resulted in suppression of MPM cell migration. Conclusion: These functional data implicating KCa1.1 in MPM cell migration support our integrative approach using MPM gene expression datasets to identify novel and potentially druggable targets. [ABSTRACT FROM AUTHOR]

Published
2016
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39. Loss of heterozygosity of the Mutated in Colorectal Cancer gene is not associated with promoter methylation in non-small cell lung cancer

Author

Poursoltan, Pirooz, primary, Currey, Nicola, additional, Pangon, Laurent, additional, van Kralingen, Christa, additional, Selinger, Christina I., additional, Mahar, Annabelle, additional, Cooper, Wendy A., additional, Kennedy, Catherine W., additional, McCaughan, Brian C., additional, Trent, Ronald, additional, and Kohonen-Corish, Maija R.J., additional

Published
2012
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41. The MARS feasibility trial: conclusions not supported by data

Author

Weder, Walter, primary, Stahel, Rolf A, additional, Baas, Paul, additional, Dafni, Urania, additional, de Perrot, Marc, additional, McCaughan, Brian C, additional, Nakano, Takashi, additional, Pass, Harvey I, additional, Robinson, Bruce WS, additional, Rusch, Valerie W, additional, Sugarbaker, David J, additional, and van Zandwijk, Nico, additional

Published
2011
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43. Readmissions After Cardiac Surgery: A 10-Year Study

Author

Bianco, Anita C., primary, Chan, Judy Y., additional, Hughes, Clifford F., additional, McCaughan, Brian C., additional, Bayfield, Matthew S., additional, Hendel, P.N., additional, Bannon, Paul G., additional, Wilson, Michael K., additional, and Vallely, Michael P., additional

Published
2011
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