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288 results on '"Yoshitaka Sekido"'

1. Aberrant expression of NPPB through YAP1 and TAZ activation in mesothelioma with Hippo pathway gene alterations

Author

Tatsuhiro Sato, Ken Akao, Ayuko Sato, Tohru Tsujimura, Satomi Mukai, and Yoshitaka Sekido

Subjects
BNP, Hippo pathway, mesothelioma, NPPB, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Mesothelioma is a neoplastic disease associated with asbestos exposure. It is highly malignant and has a poor prognosis; thus, early detection is desirable. Recent whole‐genome analysis has revealed that mesothelioma is characterized by a high frequency of mutations in a set of genes involved in the Hippo pathway, such as NF2 and LATS2. However, a rapid, simple, and precise method for finding mesothelioma with these mutations has not yet been established. Methods Clustering of Hippo pathway gene alteration groups and the differential expression of each gene in mesothelioma patients were analyzed using The Cancer Genome Atlas database. Gene expression levels in various tumors and normal tissues were analyzed using public databases. Knockdown or transient expression of YAP1 or TAZ was performed to evaluate the regulation of gene expression by these genes. NT‐proBNP was measured in the pleural effusions of 18 patients and was compared with NF2 expression in five cases where cell lines had been successfully established. Results NPPB mRNA expression was markedly higher in the group of mesothelioma patients with Hippo pathway gene mutations than in the group without them. NPPB expression was low in all normal tissues except heart, and was highest in mesothelioma. Mesothelioma patients in the high NPPB expression group had a significantly worse prognosis than those in the low NPPB expression group. NPPB expression was suppressed by knockdown of YAP1 or TAZ. NT‐proBNP was abundant in the effusions of mesothelioma patients and was particularly high in those with impaired NF2 expression. Conclusions NPPB, whose levels can be measured in pleural effusions of mesothelioma patients, has the potential to act as a biomarker to detect NF2‐Hippo pathway gene alterations and/or predict patient prognosis. Additionally, it may provide useful molecular insights for a better understanding of mesothelioma pathogenesis and for the development of novel therapies.

Published
2023
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2. SMG6 regulates DNA damage and cell survival in Hippo pathway kinase LATS2-inactivated malignant mesothelioma

Author

Koya Suzuki, Masaki Tange, Ryota Yamagishi, Hiroyuki Hanada, Satomi Mukai, Tatsuhiro Sato, Takeshi Tanaka, Tomohiro Akashi, Kenji Kadomatsu, Tohru Maeda, Takashi Miida, Ichiro Takeuchi, Hiroshi Murakami, Yoshitaka Sekido, and Yuko Murakami-Tonami

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671
Abstract

Abstract Many genes responsible for Malignant mesothelioma (MM) have been identified as tumor suppressor genes and it is difficult to target these genes directly at a molecular level. We searched for the gene which showed synthetic lethal phenotype with LATS2, one of the MM causative genes and one of the kinases in the Hippo pathway. Here we showed that knockdown of SMG6 results in synthetic lethality in LATS2-inactivated cells. We found that this synthetic lethality required the nuclear translocation of YAP1 and TAZ. Both are downstream factors of the Hippo pathway. We also demonstrated that this synthetic lethality did not require SMG6 in nonsense-mediated mRNA decay (NMD) but in regulating telomerase reverse transcriptase (TERT) activity. In addition, the RNA-dependent DNA polymerase (RdDP) activity of TERT was required for this synthetic lethal phenotype. We confirmed the inhibitory effects of LATS2 and SMG6 on cell proliferation in vivo. The result suggests an interaction between the Hippo and TERT signaling pathways. We also propose that SMG6 and TERT are novel molecular target candidates for LATS2-inactivated cancers such as MM.

Published
2022
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3. NF2 alteration in mesothelioma

Author

Yoshitaka Sekido and Tatsuhiro Sato

Subjects
mesothelioma, genome, tumor suppressor gene, NF2, Hippo pathway, Toxicology. Poisons, RA1190-1270
Abstract

The NF2 tumor suppressor gene is a frequent somatically mutated gene in mesothelioma, with 30%–40% mesotheliomas showing NF2 inactivation. NF2 encodes merlin, a member of the ezrin, radixin, and moesin (ERM) family of proteins that regulate cytoskeleton and cell signaling. Recent genome analysis revealed that NF2 alteration may be a late event in mesothelioma development, suggesting that NF2 mutation confers a more aggressive phenotype to mesothelioma cells and may not be directly caused by asbestos exposure. The Hippo tumor-suppressive and mTOR prooncogenic signaling pathways are crucial cell-signaling cascades regulated by merlin. Although the exact role and timing of NF2 inactivation in mesothelioma cells remain to be elucidated, targeting the NF2/merlin-Hippo pathway may be a new therapeutic strategy for patients with mesothelioma.

Published
2023
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4. Three newly established immortalized mesothelial cell lines exhibit morphological phenotypes corresponding to malignant mesothelioma epithelioid, intermediate, and sarcomatoid types, respectively

Author

Tatsuhiro Sato, Hayao Nakanishi, Ken Akao, Maho Okuda, Satomi Mukai, Tohru Kiyono, and Yoshitaka Sekido

Subjects
Mesothelioma, Mesothelial cell, EMT, TGF-β, IL-1β, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671
Abstract

Abstract Background Malignant mesothelioma (MM) is a very aggressive tumor that develops from mesothelial cells, mainly due to asbestos exposure. MM is categorized into three major histological subtypes: epithelioid, sarcomatoid, and biphasic, with the biphasic subtype containing both epithelioid and sarcomatoid components. Patients with sarcomatoid mesothelioma usually show a poorer prognosis than those with epithelioid mesothelioma, but it is not clear how these morphological phenotypes are determined or changed during the oncogenic transformation of mesothelial cells. Methods We introduced the E6 and E7 genes of human papillomavirus type 16 and human telomerase reverse transcriptase gene in human peritoneal mesothelial cells and established three morphologically different types of immortalized mesothelial cell lines. Results HOMC-B1 cells exhibited epithelioid morphology, HOMC-A4 cells were fibroblast-like, spindle-shaped, and HOMC-D4 cells had an intermediate morphology, indicating that these three cell lines closely mimicked the histological subtypes of MM. Gene expression profiling revealed increased expression of NOD-like receptor signaling-related genes in HOMC-A4 cells. Notably, the combination treatment of HOMC-D4 cells with TGF-β and IL-1β induced a morphological change from intermediate to sarcomatoid morphology. Conclusions Our established cell lines are useful for elucidating the fundamental mechanisms of mesothelial cell transformation and mesothelial-to-mesenchymal transition.

Published
2021
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5. Possible Therapeutic Utility of anti-Cell Adhesion Molecule 1 Antibodies for Malignant Pleural Mesothelioma

Author

Man Hagiyama, Takahiro Mimae, Akihiro Wada, Fuka Takeuchi, Azusa Yoneshige, Takao Inoue, Naoyuki Kotoku, Hironobu Hamada, Yoshitaka Sekido, Morihito Okada, and Akihiko Ito

Subjects
cell adhesion molecule 1 (CADM1), neutralizing antibody, antibody drug complex, monomethyl auristatin E (MMAE), humanized antibody, Biology (General), QH301-705.5
Abstract

Malignant pleural mesothelioma (MPM) is a highly aggressive malignant tumor, and the effective therapeutic drugs are limited. Thus, the establishment of novel therapeutic method is desired. Considerable proportion of MPMs are shown to express cell adhesion molecule 1 (CADM1), and to use CADM1 to bind to and proliferate on the pleural mesothelial surface, suggesting that CADM1 is a possible therapeutic target. Here, anti-CADM1 ectodomain chicken monoclonal antibodies, 3E1 and 9D2, were examined for their possible therapeutic utility. The full-length form of CADM1 was expressed in eight out of twelve human MPM cell lines. MPM cell lines were cultured on a confluent monolayer of mesothelial MeT-5A cells in the presence of 9D2, the neutralizing antibody. 9D2 suppressed the cell growth of CADM1-positive MPM cells with the loss and aggregation of CADM1 molecules on the MPM cell membrane, but not of CADM1-negative MPM cells. Co-addition of 3E1, lacking the neutralizing action, enhanced the growth-suppressive effect of 9D2. The two antibodies were tested as drug delivery vectors. 3E1 was converted into a humanized antibody (h3E1) and conjugated with monomethyl auristatin E (MMAE), a tubulin polymerization inhibitor. When the resulting h3E1–MMAE antibody-drug conjugate (ADC) was added to the standard cultures of CADM1-positive MPM cells, it suppressed the cell growth in a dose-dependent manner. Co-addition of 9D2 enhanced the growth-suppressive effect of h3E1–MMAE ADC. Anti-CADM1 ectodomain antibodies were suggested to serve as both antibody drugs and drug vectors in the treatment of MPM.

Published
2022
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6. Lysosomal nitric oxide determines transition from autophagy to ferroptosis after exposure to plasma-activated Ringer's lactate

Author

Li Jiang, Hao Zheng, Qinying Lyu, Shotaro Hayashi, Kotaro Sato, Yoshitaka Sekido, Kae Nakamura, Hiromasa Tanaka, Kenji Ishikawa, Hiroaki Kajiyama, Masaaki Mizuno, Masaru Hori, and Shinya Toyokuni

Subjects
Ferroptosis, Non-thermal plasma-activated Ringer's lactate, Malignant mesothelioma, Nitric oxide, Autophagy, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Non-thermal plasma (NTP), an engineered technology to generate reactive species, induces ferroptosis and/or apoptosis specifically in various-type cancer cells. NTP-activated Ringer's lactate (PAL) is another modality for cancer therapy at preclinical stage. Here we found that PAL induces selective ferroptosis of malignant mesothelioma (MM) cells, where non-targeted metabolome screening identified upregulated citrulline-nitric oxide (.NO) cycle as a PAL target. .NO probe detected biphasic peaks transiently at PAL exposure with time-dependent increase, which was responsible for inducible . NO synthase (iNOS) overexpression through NF-κB activation. .NO and lipid peroxidation occupied lysosomes as a major compartment with increased TFEB expression. Not only ferrostatin-1 but inhibitors for . NO and/or iNOS could suppress this ferroptosis. PAL-induced ferroptosis accompanied autophagic process in the early phase, as demonstrated by an increase in essential amino acids, LC3B-II, p62 and LAMP1, transforming into the later phase with boosted lipid peroxidation. Therefore, .NO-mediated lysosomal impairment is central in PAL-induced ferroptosis.

Published
2021
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7. Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia

Author

Zan Li, Li Jiang, Shan Hwu Chew, Tasuku Hirayama, Yoshitaka Sekido, and Shinya Toyokuni

Subjects
Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Hypoxia and acidity provide microenvironment for selection under evolutionary pressure and proliferation in cancer cells. Carbonic anhydrases (CAs) are a superfamily of metalloenzymes present in all life kingdoms, equilibrating the reactions among CO2, bicarbonate and H+. CA9, a membrane-associated α-CA, has been a drug target for various cancers. Whereas iron is essential not only for cancer cells but also for all the lives on earth, little is known on the association among hypoxia, iron metabolism, extracellular acidity and redox regulation. Malignant mesothelioma (MM), an aggressive tumor with poor prognosis, is an intriguing model in that asbestos-associated pathogenesis includes excess iron environment during carcinogenesis. Re-analysis of rat asbestos-induced MM model revealed an inverse association between high CA9 expression and survival. Here we used human MMs to identify the molecular events surrounding CA9 from the viewpoint of iron metabolism. CA9 expression was significantly higher in MM cells than in MeT-5A mesothelial cells, which was further amplified under hypoxia (1%O2) with increased catalytic Fe(II). CA9 suppression by inhibitors (S4 and U104) decreased viability and migration of MM cells, accompanied by overexpression of TFRC, IREB1/2 and FPN1(SLC40A1) and by downregulation of FTH/FTL. This expressional pattern was similar to that of erastin-induced ferroptosis in the same cells. Furthermore, we observed mitochondrial fission and enhanced autophagy with increased catalytic Fe(II) in both mitochondria and lysosomes after CA9 inhibition, accompanied by increased peroxides, mitochondrial O2− and lipid peroxidation. The eventual cell death was significantly inhibited by deferoxamine, ferrostatin-1 and Z-VAD-FMK, suggesting a mixed cell death of ferroptosis and apoptosis. Therefore, CA9 plays a role in equilibrating among hypoxia, iron metabolism and redox regulation in MM cells. Keywords: Carbonic anhydrase, Malignant mesothelioma, Iron metabolism, Tumor biology, Apoptosis, Ferroptosis, Catalytic Fe(II)

Published
2019
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8. Merlin/NF2-Lin28B-let-7 Is a Tumor-Suppressive Pathway that Is Cell-Density Dependent and Hippo Independent

Author

Hiroki Hikasa, Yoshitaka Sekido, and Akira Suzuki

Subjects
Merlin/NF2, Lin28B, let-7, cell contact, Hippo pathway, microRNA, Biology (General), QH301-705.5
Abstract

Contact inhibition of proliferation is critical for tissue organization, and its dysregulation contributes to tumorigenesis. Merlin/NF2 is a tumor suppressor that governs contact inhibition. Although Merlin/NF2 inhibits YAP1 and TAZ, which are paralogous Hippo pathway transcriptional co-activators and oncoproteins, it is not fully understood how Merlin/NF2-mediated signal transduction triggered by cell-cell contact exerts tumor suppression. Here, we identify Lin28B, an inhibitor of let-7 microRNAs (miRNAs), as an important downstream target of Merlin/NF2. Functional studies revealed that, at low cell density, Merlin/NF2 is phosphorylated and does not bind to Lin28B, allowing Lin28B to enter the nucleus, bind to pri-let-7 miRNAs, and inhibit their maturation in a YAP1/TAZ-independent manner. This inhibition of pri-let-7 maturation then promotes cell growth. However, cell-cell contact triggers Merlin/NF2 dephosphorylation, which sequesters Lin28B in the cytoplasm and permits pri-let-7 maturation. Our results reveal that Merlin/NF2-mediated signaling drives a tumor-suppressive pathway that is cell-density dependent and Hippo independent.

Published
2016
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9. Collateral chemoresistance to anti-microtubule agents in a lung cancer cell line with acquired resistance to erlotinib.

Author

Hiroshi Mizuuchi, Kenichi Suda, Katsuaki Sato, Shuta Tomida, Yoshihiko Fujita, Yoshihisa Kobayashi, Yoshihiko Maehara, Yoshitaka Sekido, Kazuto Nishio, and Tetsuya Mitsudomi

Subjects
Medicine, Science
Abstract

Various alterations underlying acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been described. Although treatment strategies specific for these mechanisms are under development, cytotoxic agents are currently employed to treat many patients following failure of EGFR-TKIs. However, the effect of TKI resistance on sensitivity to these cytotoxic agents is mostly unclear. This study investigated the sensitivity of erlotinib-resistant tumor cells to five cytotoxic agents using an in vitro EGFR-TKI-resistant model. Four erlotinib-sensitive lung adenocarcinoma cell lines and their resistant derivatives were tested. Of the resistant cell lines, all but one showed a similar sensitivity to the tested drugs as their parental cells. HCC4006ER cells with epithelial mesenchymal transition features acquired resistance to the three microtubule-targeting agents, docetaxel, paclitaxel and vinorelbine, but not to cisplatin and gemcitabine. Gene expression array and immunoblotting demonstrated that ATP-binding cassette subfamily B, member 1 (ABCB1) was up-regulated in HCC4006ER cells. ABCB1 knockdown by siRNA partially restored sensitivity to the anti-microtubule agents but not to erlotinib. Moreover, the histone deacetylase inhibitor entinostat sensitized HCC4006ER cells to anti-microtubule agents through ABCB1 suppression. Our study indicates that sensitivity of tumor cells to cytotoxic agents in general does not change before and after failure of EGFR-TKIs. However, we describe that two different molecular alterations confer acquired resistance to EGFR-TKIs and cytotoxic agents, respectively. This phenomenon should be kept in mind in selection of subsequent therapy after failure of EGFR-TKIs.

Published
2015
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10. Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer.

Author

Shinya Akatsuka, Yoriko Yamashita, Hiroki Ohara, Yu-Ting Liu, Masashi Izumiya, Koichiro Abe, Masako Ochiai, Li Jiang, Hirotaka Nagai, Yasumasa Okazaki, Hideki Murakami, Yoshitaka Sekido, Eri Arai, Yae Kanai, Okio Hino, Takashi Takahashi, Hitoshi Nakagama, and Shinya Toyokuni

Subjects
Medicine, Science
Abstract

Iron overload has been associated with carcinogenesis in humans. Intraperitoneal administration of ferric nitrilotriacetate initiates a Fenton reaction in renal proximal tubules of rodents that ultimately leads to a high incidence of renal cell carcinoma (RCC) after repeated treatments. We performed high-resolution microarray comparative genomic hybridization to identify characteristics in the genomic profiles of this oxidative stress-induced rat RCCs. The results revealed extensive large-scale genomic alterations with a preference for deletions. Deletions and amplifications were numerous and sometimes fragmented, demonstrating that a Fenton reaction is a cause of such genomic alterations in vivo. Frequency plotting indicated that two of the most commonly altered loci corresponded to a Cdkn2a/2b deletion and a Met amplification. Tumor sizes were proportionally associated with Met expression and/or amplification, and clustering analysis confirmed our results. Furthermore, we developed a procedure to compare whole genomic patterns of the copy number alterations among different species based on chromosomal syntenic relationship. Patterns of the rat RCCs showed the strongest similarity to the human RCCs among five types of human cancers, followed by human malignant mesothelioma, an iron overload-associated cancer. Therefore, an iron-dependent Fenton chemical reaction causes large-scale genomic alterations during carcinogenesis, which may result in distinct genomic profiles. Based on the characteristics of extensive genome alterations in human cancer, our results suggest that this chemical reaction may play a major role during human carcinogenesis.

Published
2012
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11. Downregulation of histone H3 lysine 9 methyltransferase G9a induces centrosome disruption and chromosome instability in cancer cells.

Author

Yutaka Kondo, Lanlan Shen, Saira Ahmed, Yanis Boumber, Yoshitaka Sekido, Bassem R Haddad, and Jean-Pierre J Issa

Subjects
Medicine, Science
Abstract

Modifications of the histone amino-terminal tails affect access of regulatory factors and complexes to chromatin and thereby influence biological processes. Cancer cells are characterized by prominent epigenetic dysregulation, including histone modifications. However, the functional roles of the histone methyltransferases (HMT) in cancer remain unclear.We studied RNAi-based inhibition (knockdown, KD) of 2 different H3K9 HMTs, SUV39H1 and G9a. Knockdown of the 2 HMTs in PC3 cancer cell line markedly inhibited cell growth and caused profound morphological changes with loss of telomerase activity and shortened telomeres. SUV39H1 KD cells showed substantial increase in G2/M fraction. G9a KD cells showed increased DNA content (1.7-fold in 2 independent clones) compared with FACS analyses to control. Karyotype analyses showed that this was due to an increased number of chromosomes (from 61 to 102) in G9a KD cells compared to parental PC3. Intriguingly, we found abnormal centrosome morphology and number in about 25% of the G9a KD cells, while centrosomes were morphologically normal in control cells. Microarray analyses after KD of SUV39H1 or G9a showed very few genes up-regulated among the 39,000 genes. The silenced tumor-suppressor genes p16 and RASSF1A were not activated in KD cells.These data suggest that the 2 HMTs, SUV39H1 and G9a are required to perpetuate the malignant phenotype. Furthermore, G9a plays a critical role in regulating centrosome duplication presumably through chromatin structure rather than through affecting gene expression in cancer cells. Targeting these histone methyltransferases may be of therapeutic benefit in cancers.

Published
2008
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13. Supplementary Figures 1-9 from Silencing of SmgGDS, a Novel mTORC1 Inducer That Binds to RHEBs, Inhibits Malignant Mesothelioma Cell Proliferation

Author

Yoshitaka Sekido, Seisuke Hattori, Yoshio Shibagaki, Wataru Shimono, Okio Hino, Toshiyuki Kobayashi, Ken Akao, Emi Mishiro-Sato, Haruna Ikeda, Satomi Mukai, and Tatsuhiro Sato

Abstract

Figure S1. RHEB mRNA expression in different types of cancer. Figure S2. In vivo growth of MeT-5A mesothelial cells expressing exogenous RHEBL1. Figure S3. RHEBL1 binds to SmgGDS. Figure S4. SmgGDS knockdown suppresses the proliferation of mesothelial cells expressing exogenous RHEBL1. Figure S5. SmgGDS knockdown suppresses the growth of PTEN-deficient MM cells in vitro. Figure S6. Subcellular RHEBL1 localization. Figure S7. SmgGDS knockdown alters RHEBL1 localization in PTEN-deficient MM cells. Figure S8. Amino acid stimulation does not affect RHEBL1 subcellular localization. Figure S9. RHEBL1 farnesylation is essential for SmgGDS binding.

Published
2023

14. Data from Silencing of SmgGDS, a Novel mTORC1 Inducer That Binds to RHEBs, Inhibits Malignant Mesothelioma Cell Proliferation

Author

Yoshitaka Sekido, Seisuke Hattori, Yoshio Shibagaki, Wataru Shimono, Okio Hino, Toshiyuki Kobayashi, Ken Akao, Emi Mishiro-Sato, Haruna Ikeda, Satomi Mukai, and Tatsuhiro Sato

Abstract

Malignant mesothelioma (MM) is an aggressive tumor that typically develops after a long latency following asbestos exposure. Although mechanistic target of rapamycin complex 1 (mTORC1) activation enhances MM cell growth, the mTORC1 inhibitor everolimus has shown limited efficacy in clinical trials of MM patients. We explored the mechanism underlying mTORC1 activation in MM cells and its effects on cell proliferation and progression. Analysis of the expression profiles of 87 MMs from The Cancer Genome Atlas revealed that 40 samples (46%) displayed altered expression of RPTOR (mTORC1 component) and genes immediately upstream that activate mTORC1. Among them, we focused on RHEB and RHEBL1, which encode direct activators of mTORC1. Exogenous RHEBL1 expression enhanced MM cell growth, indicating that RHEB–mTORC1 signaling acts as a pro-oncogenic cascade. We investigated molecules that directly activate RHEBs, identifying SmgGDS as a novel RHEB-binding protein. SmgGDS knockdown reduced mTORC1 activation and inhibited the proliferation of MM cells with mTORC1 activation. Interestingly, SmgGDS displayed high binding affinity with inactive GDP-bound RHEBL1, and its knockdown reduced cytosolic RHEBL1 without affecting its activation. These findings suggest that SmgGDS retains GDP-bound RHEBs in the cytosol, whereas GTP-bound RHEBs are localized on intracellular membranes to promote mTORC1 activation. We revealed a novel role for SmgGDS in the RHEB–mTORC1 pathway and its potential as a therapeutic target in MM with aberrant mTORC1 activation.Implications:Our data showing that SmgGDS regulates RHEB localization to activate mTORC1 indicate that SmgGDS can be used as a new therapeutic target for MM exhibiting mTORC1 activation.

Published
2023

15. Supplementary Figure S5 from A Novel Therapeutic Strategy Targeting the Mesenchymal Phenotype of Malignant Pleural Mesothelioma by Suppressing LSD1

Author

Kazuhisa Takahashi, Yoshitaka Sekido, Okio Hino, Masaaki Abe, Kenji Suzuki, Kazuya Takamochi, Naoko Shimada, Ryo Ko, Tetsuhiko Asao, Kenta Izumi, Naohisa Matsumoto, Daisuke Hayakawa, Moulid Hidayat, Wira Winardi, Yoichiro Mitsuishi, Fumiyuki Takahashi, Ken Tajima, and Aditya Wirawan

Abstract

Supplementary Figure S5 shows role of MFGE8 in MPM.

Published
2023

16. Supplementary Figure Legends from A Novel Therapeutic Strategy Targeting the Mesenchymal Phenotype of Malignant Pleural Mesothelioma by Suppressing LSD1

Author

Kazuhisa Takahashi, Yoshitaka Sekido, Okio Hino, Masaaki Abe, Kenji Suzuki, Kazuya Takamochi, Naoko Shimada, Ryo Ko, Tetsuhiko Asao, Kenta Izumi, Naohisa Matsumoto, Daisuke Hayakawa, Moulid Hidayat, Wira Winardi, Yoichiro Mitsuishi, Fumiyuki Takahashi, Ken Tajima, and Aditya Wirawan

Abstract

Supplementary Figure Legends

Published
2023

18. Table S6 from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author

Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak

Abstract

Table S6 contains results from the analysis of DNA methylation in SETD2 mutated and BAP1 inactivated samples.

Published
2023

19. Supplementary Figure 2 from Combined Therapy with Mutant-Selective EGFR Inhibitor and Met Kinase Inhibitor for Overcoming Erlotinib Resistance in EGFR-Mutant Lung Cancer

Author

Seiji Yano, Toshimitsu Uenaka, Yoshitaka Sekido, Tetsuya Mitsudomi, Kenichi Suda, Kunio Matsumoto, Takahiro Nakamura, Kenji Kita, Takako Sano, Daisuke Ishikawa, Shigeki Nanjo, Tadaaki Yamada, Shinji Takeuchi, and Takayuki Nakagawa

Abstract

PDF file, 115K, Supplementary Figure S2 E7050 inhibits tumor cell motility induced by HGF overexpression.

Published
2023

20. Supplementary Table S1 from A Novel Therapeutic Strategy Targeting the Mesenchymal Phenotype of Malignant Pleural Mesothelioma by Suppressing LSD1

Author

Kazuhisa Takahashi, Yoshitaka Sekido, Okio Hino, Masaaki Abe, Kenji Suzuki, Kazuya Takamochi, Naoko Shimada, Ryo Ko, Tetsuhiko Asao, Kenta Izumi, Naohisa Matsumoto, Daisuke Hayakawa, Moulid Hidayat, Wira Winardi, Yoichiro Mitsuishi, Fumiyuki Takahashi, Ken Tajima, and Aditya Wirawan

Abstract

Supplementary Table S1 shows the selected genes with statistically significant changes in transcriptome analysis using two different shRNA constructs.

Published
2023

21. Supplementary Figure 6 from Combined Therapy with Mutant-Selective EGFR Inhibitor and Met Kinase Inhibitor for Overcoming Erlotinib Resistance in EGFR-Mutant Lung Cancer

Author

Seiji Yano, Toshimitsu Uenaka, Yoshitaka Sekido, Tetsuya Mitsudomi, Kenichi Suda, Kunio Matsumoto, Takahiro Nakamura, Kenji Kita, Takako Sano, Daisuke Ishikawa, Shigeki Nanjo, Tadaaki Yamada, Shinji Takeuchi, and Takayuki Nakagawa

Abstract

PDF file, 138K, Supplementary Figure S6 Treatment with WZ4002 and/or E7050 does not induce apoptosis in vivo.

Published
2023

22. Data from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author

Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak

Abstract

Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options.Significance:Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM.See related commentary by Aggarwal and Albelda, p. 1508.This article is highlighted in the In This Issue feature, p. 1494

Published
2023

23. Supplementary Figure 3 from Combined Therapy with Mutant-Selective EGFR Inhibitor and Met Kinase Inhibitor for Overcoming Erlotinib Resistance in EGFR-Mutant Lung Cancer

Author

Seiji Yano, Toshimitsu Uenaka, Yoshitaka Sekido, Tetsuya Mitsudomi, Kenichi Suda, Kunio Matsumoto, Takahiro Nakamura, Kenji Kita, Takako Sano, Daisuke Ishikawa, Shigeki Nanjo, Tadaaki Yamada, Shinji Takeuchi, and Takayuki Nakagawa

Abstract

PDF file, 181K, Supplementary Figure S3 Sustained inhibition of Akt and Erk phosphorylation by combining WZ4002 and E7050.

Published
2023

24. Supplementary Figure 4 from Combined Therapy with Mutant-Selective EGFR Inhibitor and Met Kinase Inhibitor for Overcoming Erlotinib Resistance in EGFR-Mutant Lung Cancer

Author

Seiji Yano, Toshimitsu Uenaka, Yoshitaka Sekido, Tetsuya Mitsudomi, Kenichi Suda, Kunio Matsumoto, Takahiro Nakamura, Kenji Kita, Takako Sano, Daisuke Ishikawa, Shigeki Nanjo, Tadaaki Yamada, Shinji Takeuchi, and Takayuki Nakagawa

Abstract

PDF file, 423K, Supplementary Figure S4 Cytostatic effects of WZ4002 and E7050 treatment.

Published
2023

25. Supplementary Figure 5 from Combined Therapy with Mutant-Selective EGFR Inhibitor and Met Kinase Inhibitor for Overcoming Erlotinib Resistance in EGFR-Mutant Lung Cancer

Author

Seiji Yano, Toshimitsu Uenaka, Yoshitaka Sekido, Tetsuya Mitsudomi, Kenichi Suda, Kunio Matsumoto, Takahiro Nakamura, Kenji Kita, Takako Sano, Daisuke Ishikawa, Shigeki Nanjo, Tadaaki Yamada, Shinji Takeuchi, and Takayuki Nakagawa

Abstract

PDF file, 315K, Supplementary Figure S5 Relative body weight of mice during treatment with WZ4002 and/or E7050.

Published
2023

26. Supplementary Data from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author

Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak

Abstract

Supplementary materials and methods, as well as supplementary figures S1-S7.

Published
2023

27. Supplementary Table 1 from Combined Therapy with Mutant-Selective EGFR Inhibitor and Met Kinase Inhibitor for Overcoming Erlotinib Resistance in EGFR-Mutant Lung Cancer

Author

Seiji Yano, Toshimitsu Uenaka, Yoshitaka Sekido, Tetsuya Mitsudomi, Kenichi Suda, Kunio Matsumoto, Takahiro Nakamura, Kenji Kita, Takako Sano, Daisuke Ishikawa, Shigeki Nanjo, Tadaaki Yamada, Shinji Takeuchi, and Takayuki Nakagawa

Abstract

PDF file, 40K, Supplementary Table S1 IC50 values of each compound in MTT assay.

Published
2023

28. Data from Combined Therapy with Mutant-Selective EGFR Inhibitor and Met Kinase Inhibitor for Overcoming Erlotinib Resistance in EGFR-Mutant Lung Cancer

Author

Seiji Yano, Toshimitsu Uenaka, Yoshitaka Sekido, Tetsuya Mitsudomi, Kenichi Suda, Kunio Matsumoto, Takahiro Nakamura, Kenji Kita, Takako Sano, Daisuke Ishikawa, Shigeki Nanjo, Tadaaki Yamada, Shinji Takeuchi, and Takayuki Nakagawa

Abstract

Although the EGF receptor tyrosine kinase inhibitors (EGFR-TKI) erlotinib and gefitinib have shown dramatic effects against EGFR mutant lung cancer, patients become resistant by various mechanisms, including gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression, thereafter relapsing. Thus, it is urgent to develop novel agents to overcome EGFR-TKI resistance. We have tested the effects of the mutant-selective EGFR-TKI WZ4002 and the mutant-selective Met-TKI E7050 on 3 EGFR mutant lung cancer cell lines resistant to erlotinib by different mechanisms: PC-9/HGF cells with an exon 19 deletion, H1975 with an L858R mutation, and HCC827ER with an exon 19 deletion, with acquired resistance to erlotinib because of HGF gene transfection, gatekeeper T790M mutation, and Met amplification, respectively. WZ4002 inhibited the growth of H1975 cells with a gatekeeper T790M mutation, but did not inhibit the growth of HCC827ER and PC-9/HGF cells. HGF triggered the resistance of H1975 cells to WZ4002, whereas E7050 sensitized HCC827ER, PC-9/HGF, and HGF-treated H1975 cells to WZ4002, inhibiting EGFR and Met phosphorylation and their downstream molecules. Combined treatment potently inhibited the growth of tumors induced in severe-combined immunodeficient mice by H1975, HCC827ER, and PC-9/HGF cells, without any marked adverse events. These therapeutic effects were associated with the inhibition of EGFR and Met phosphorylation in vivo. The combination of a mutant-selective EGFR-TKI and a Met-TKI was effective in suppressing the growth of erlotinib-resistant tumors caused by gatekeeper T790M mutation, Met amplification, and HGF overexpression. Further evaluations in clinical trials are warranted. Mol Cancer Ther; 11(10); 2149–57. ©2012 AACR.

Published
2023

29. Data from A Novel Therapeutic Strategy Targeting the Mesenchymal Phenotype of Malignant Pleural Mesothelioma by Suppressing LSD1

Author

Kazuhisa Takahashi, Yoshitaka Sekido, Okio Hino, Masaaki Abe, Kenji Suzuki, Kazuya Takamochi, Naoko Shimada, Ryo Ko, Tetsuhiko Asao, Kenta Izumi, Naohisa Matsumoto, Daisuke Hayakawa, Moulid Hidayat, Wira Winardi, Yoichiro Mitsuishi, Fumiyuki Takahashi, Ken Tajima, and Aditya Wirawan

Abstract

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that has a low overall survival; however, no significant treatment advances have been made in the past 15 years. Large-scale molecular studies have identified a poor prognostic subset of MPM linked to the epithelial–mesenchymal transition (EMT) that may contribute toward resistance to chemotherapy, suggesting that EMT could be targeted to treat patients with MPM. Previously, we reported that histone modifiers regulating EMT could be therapeutic targets; therefore, in this study, we investigated whether targeting lysine-specific demethylase 1 (LSD1/KDM1), a histone-modifying enzyme responsible for demethylating histone H3 lysine 4 and lysine 9, could represent a novel therapeutic strategy for MPM. We suppressed LSD1 and investigated the EMT phenotype using EMT marker expression and wound-healing assay; and chemosensitivity using apoptosis assay. We found that suppressing LSD1 induces an epithelial phenotype in sarcomatoid MPM cells, while attenuating the mesenchymal phenotype sensitized MPM cells to cisplatin-induced apoptosis. Subsequent genome-wide identification, comprehensive microarray analysis, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) to assess genome-wide changes in chromatin accessibility suggested that LSD1 directly regulates milk fat globulin protein E8 (MFGE8), an integrin ligand that is involved in the FAK pathway. Furthermore, we found that LSD1 regulates the mesenchymal phenotype and apoptosis by activating the FAK–AKT–GSK3β pathway via a positive feedback loop involving MFGE8 and Snail expression, thereby leading to cisplatin resistance.Implications:This study suggests that LSD1 regulates the mesenchymal phenotype and apoptosis, and that LSD1 inhibitors could be combined with the cisplatin as a novel therapy for patients with MPM.

Published
2023

31. CCR Translation for This Article from Reciprocal and Complementary Role of MET Amplification and EGFR T790M Mutation in Acquired Resistance to Kinase Inhibitors in Lung Cancer

Author

Tetsuya Mitsudomi, Yasushi Yatabe, Yoshihiko Maehara, Yoshitaka Sekido, Hirotaka Osada, Kenji Tomizawa, Tatsuya Katayama, Isao Murakami, and Kenichi Suda

Abstract

CCR Translation for This Article from Reciprocal and Complementary Role of MET Amplification and EGFR T790M Mutation in Acquired Resistance to Kinase Inhibitors in Lung Cancer

Published
2023

32. Data from Reciprocal and Complementary Role of MET Amplification and EGFR T790M Mutation in Acquired Resistance to Kinase Inhibitors in Lung Cancer

Author

Tetsuya Mitsudomi, Yasushi Yatabe, Yoshihiko Maehara, Yoshitaka Sekido, Hirotaka Osada, Kenji Tomizawa, Tatsuya Katayama, Isao Murakami, and Kenichi Suda

Abstract

Purpose: In epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer patients, acquired resistance develops almost inevitably and this limits the improvement in patient outcomes. EGFR T790M mutation and MET amplification are the two main mechanisms underlying this resistance, but the relationship between these two mechanisms is unclear. In this study, we explored their relationship using in vitro models and autopsy specimens.Experimental Design: Erlotinib-resistant HCC827 (HCC827ER) cells were developed by chronic exposure to erlotinib at increasing concentrations. HCC827EPR cells were also developed by chronic exposure to erlotinib in the presence of PHA-665,752 (a MET TKI). The erlotinib-resistant mechanisms of these cells were analyzed. In addition, 33 autopsy tumor samples from 6 lung adenocarcinoma patients harboring multiple gefitinib-refractory tumors were analyzed.Results: HCC827ER developed MET amplification, and clinically relevant resistance occurred at ≥4-fold MET gene copy number gain (CNG). By contrast, HCC827EPR developed T790M without MET CNG. Of six patients harboring gefitinib-refractory tumors, three exhibited T790M only, one exhibited MET amplification only, and the other two exhibited T790M and/or MET amplification depending on the lesion sites. In these gefitinib-refractory tumors, T790M developed in 93% (14 of 15) of tumors without MET gene CNGs, in 80% (4 of 5) of tumors with moderate MET gene CNGs (MET amplification (≥4-fold).Conclusions: These results indicate a reciprocal and complementary relationship between T790M and MET amplification and the necessity of concurrent inhibition of both for further improving patient outcomes. Clin Cancer Res; 16(22); 5489–98. ©2010 AACR.

Published
2023

36. Data from Lineage-Specific Dependency of Lung Adenocarcinomas on the Lung Development Regulator TTF-1

Author

Takashi Takahashi, Yasushi Yatabe, Mitsune Tanimoto, Yoshitaka Sekido, Tetsuya Mitsudomi, Hideo Matsubara, Takayuki Kosaka, Hirotaka Osada, Yukako Shimada, Shuta Tomida, Ken Maeno, Ayumu Taguchi, Keiko Shinjo, Kiyoshi Yanagisawa, and Hisaaki Tanaka

Abstract

Emerging evidence, although currently very sparse, suggests the presence of “lineage-specific dependency” in the survival mechanisms of certain cancers. TTF-1 has a decisive role as a master regulatory transcription factor in lung development and in the maintenance of the functions of terminal respiratory unit (TRU) cells. We show that a subset of lung adenocarcinoma cell lines expressing TTF-1, which presumably represent those derived from the TRU lineage, exhibit marked dependence on the persistent expression of TTF-1. The inhibition of TTF-1 by RNA interference (RNAi) significantly and specifically induced growth inhibition and apoptosis in these adenocarcinoma cell lines. Furthermore, a fraction of TTF-1–expressing tumors and cell lines displayed an increase in the gene dosage of TTF-1 in the analysis of 214 patients with non–small-cell lung cancer, including 174 adenocarcinomas, showing a tendency of higher frequency of increased gene copies at metastatic sites than at primary sites (P = 0.07, by two-sided Fisher's exact test). These findings strongly suggest that in addition to the development and maintenance of TRU lineages in normal lung, sustained TTF-1 expression may be crucial for the survival of a subset of adenocarcinomas that express TTF-1, providing credence for the lineage-specific dependency model. [Cancer Res 2007;67(13):6007–11]

Published
2023

39. Supplementary Methods and Figures 1-2 from Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer

Author

Takashi Takahashi, Yoshitaka Sekido, Yutaka Kondo, Hideki Murakami, Toshiyuki Takeuchi, Yoshio Tatematsu, Yasushi Yatabe, Shuta Tomida, and Hirotaka Osada

Abstract

Supplementary Methods and Figures 1-2 from Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer

Published
2023

40. Data from A Polycistronic MicroRNA Cluster, miR-17-92, Is Overexpressed in Human Lung Cancers and Enhances Cell Proliferation

Author

Takashi Takahashi, Yoshitaka Sekido, Katsunobu Kawahara, Yasushi Yatabe, Shuta Tomida, Kiyoshi Yanagisawa, Hideki Yamada, Yoshio Tatematsu, Hirotaka Osada, and Yoji Hayashita

Abstract

MicroRNAs (miRNAs) are small noncoding RNAs, thought to be involved in physiologic and developmental processes by negatively regulating expression of target genes. We have previously reported frequent down-regulation of the let-7 miRNA family in lung cancers and, in the present study, assessed alteration in a panel of 19 lung cancer cell lines. As a result, we found for the first time that the miR-17-92 cluster, which comprises seven miRNAs and resides in intron 3 of the C13orf25 gene at 13q31.3, is markedly overexpressed in lung cancers, especially with small-cell lung cancer histology. Southern blot analysis revealed the presence of increased gene copy numbers of the miRNA cluster in a fraction of lung cancer cell lines with overexpression. In addition, we were able to show predominant localization of C13orf25 transcripts within the nucleus and introduction of the expression construct of the miR-17-92 cluster, but not the putative open reading frame of C13orf25, enhancing lung cancer cell growth. These findings clearly suggest that marked overexpression of the miR-17-92 cluster with occasional gene amplification may play a role in the development of lung cancers, especially in their most aggressive form, small-cell lung cancer, and that the C13orf25 gene may well be serving as a vehicle in this regard.

Published
2023

45. Supplementary Figure 1 from Lineage-Specific Dependency of Lung Adenocarcinomas on the Lung Development Regulator TTF-1

Author

Takashi Takahashi, Yasushi Yatabe, Mitsune Tanimoto, Yoshitaka Sekido, Tetsuya Mitsudomi, Hideo Matsubara, Takayuki Kosaka, Hirotaka Osada, Yukako Shimada, Shuta Tomida, Ken Maeno, Ayumu Taguchi, Keiko Shinjo, Kiyoshi Yanagisawa, and Hisaaki Tanaka

Abstract

Supplementary Figure 1 from Lineage-Specific Dependency of Lung Adenocarcinomas on the Lung Development Regulator TTF-1

Published
2023

47. Supplementary Figures 1 - 5, Table 1 from EGFR-TKI Resistance Due to BIM Polymorphism Can Be Circumvented in Combination with HDAC Inhibition

Author

Seiji Yano, Yoshitaka Sekido, Yoshinori Hasegawa, Mitsuo Sato, Daisuke Ishikawa, Shigeki Nanjo, Takako Sano, Hiromichi Ebi, Tadaaki Yamada, Shinji Takeuchi, and Takayuki Nakagawa

Abstract

PDF file - 785K, Supplementary Figure 1. Expression of total BIM and ratio of BIM isoforms in NSCLC cell lines. Supplementary Figure 2. Flow cytometric analysis showing that EGFR mutated cell lines carrying the BIM polymorphism have low susceptibility to gefitinib-induced apoptosis. Supplementary Figure 3. Vorinostat-induced up-regulation of BIM enhances apoptosis in the HCC2279 cell line with the BIM polymorphism.Supplementary Figure 4. Knockdown or overexpression of BIM affects activation of caspase-3/7 induced by gefitinib and vorinostat in EGFR mutant cells with BIM polymorphism. Supplementary Figure 5. Detection of BIM polymorphism in human peripheral blood mononuclear cells (PBMC) and serum. Supplementary Table 1. Status of EGFR mutation and BIM polymorphism in NSCLC cell lines.

Published
2023

48. Supplementary Information from Lineage-Specific Dependency of Lung Adenocarcinomas on the Lung Development Regulator TTF-1

Author

Takashi Takahashi, Yasushi Yatabe, Mitsune Tanimoto, Yoshitaka Sekido, Tetsuya Mitsudomi, Hideo Matsubara, Takayuki Kosaka, Hirotaka Osada, Yukako Shimada, Shuta Tomida, Ken Maeno, Ayumu Taguchi, Keiko Shinjo, Kiyoshi Yanagisawa, and Hisaaki Tanaka

Abstract

Supplementary Information from Lineage-Specific Dependency of Lung Adenocarcinomas on the Lung Development Regulator TTF-1

Published
2023

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