71 results on '"Yiyu Dong"'
Search Results
2. ΔNp63 Inhibits Oxidative Stress-Induced Cell Death, Including Ferroptosis, and Cooperates with the BCL-2 Family to Promote Clonogenic Survival
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Gary X. Wang, Ho-Chou Tu, Yiyu Dong, Anders Jacobsen Skanderup, Yufeng Wang, Shugaku Takeda, Yogesh Tengarai Ganesan, Song Han, Han Liu, James J. Hsieh, and Emily H. Cheng
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Biology (General) ,QH301-705.5 - Abstract
Summary: The BCL-2 family proteins are central regulators of apoptosis. However, cells deficient for BAX and BAK or overexpressing BCL-2 still succumb to oxidative stress upon DNA damage or matrix detachment. Here, we show that ΔNp63α overexpression protects cells from oxidative stress induced by oxidants, DNA damage, anoikis, or ferroptosis-inducing agents. Conversely, ΔNp63α deficiency increases oxidative stress. Mechanistically, ΔNp63α orchestrates redox homeostasis through transcriptional control of glutathione biogenesis, utilization, and regeneration. Analysis of a lung squamous cell carcinoma dataset from The Cancer Genome Atlas (TCGA) reveals that TP63 amplification/overexpression upregulates the glutathione metabolism pathway in primary human tumors. Strikingly, overexpression of ΔNp63α promotes clonogenic survival of p53−/−Bax−/−Bak−/− cells against DNA damage. Furthermore, co-expression of BCL-2 and ΔNp63α confers clonogenic survival against matrix detachment, disrupts the luminal clearance of mammary acini, and promotes cancer metastasis. Our findings highlight the need for a simultaneous blockade of apoptosis and oxidative stress to promote long-term cellular well-being. : Apoptosis-defective cells remain vulnerable to oxidative stress, which limits long-term survival. Wang et al. identify ΔNp63α as a central regulator of redox homeostasis through transcriptional control of a tightly coupled glutathione metabolic circuit. ΔNp63α alleviates oxidative stress and cooperates with the BCL-2 family to promote both long-term cellular well-being and cancer metastasis. Keywords: oxidative stress, ROS, apoptosis, necrosis, programmed necrotic death, TP63, BCL-2, ferroptosis, redox, glutathione metabolism
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- 2017
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3. Targeting the differential addiction to anti-apoptotic BCL-2 family for cancer therapy
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Akane Inoue-Yamauchi, Paul S. Jeng, Kwanghee Kim, Hui-Chen Chen, Song Han, Yogesh Tengarai Ganesan, Kota Ishizawa, Sylvia Jebiwott, Yiyu Dong, Maria C. Pietanza, Matthew D. Hellmann, Mark G. Kris, James J. Hsieh, and Emily H. Cheng
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Science - Abstract
Small cell lung cancer cells (SCLC) are differentially sensitive to inhibitors of the BCL-2 family. Here the authors analyse the response to BH3 mimetics in SCLC, delineate patterns of expression of apoptotic proteins correlated with differential sensitivities and demonstrate a synergistic anti-tumour activity between ABT-199 and anthracyclines or CDK9 inhibitors.
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- 2017
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4. Analysis of renal cancer cell lines from two major resources enables genomics-guided cell line selection
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Rileen Sinha, Andrew G. Winer, Michael Chevinsky, Christopher Jakubowski, Ying-Bei Chen, Yiyu Dong, Satish K. Tickoo, Victor E. Reuter, Paul Russo, Jonathan A. Coleman, Chris Sander, James J. Hsieh, and A. Ari Hakimi
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Science - Abstract
Cell lines are central to cancer research, but knowing which cell lines are the best representative of actual tumours is a major challenge. Here the authors provide a resource assessment of 65 renal cell lines to assist researchers in selecting suitable lines for studying specific renal carcinoma subtypes.
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- 2017
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5. The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma
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Amrita M. Nargund, Can G. Pham, Yiyu Dong, Patricia I. Wang, Hatice U. Osmangeyoglu, Yuchen Xie, Omer Aras, Song Han, Toshinao Oyama, Shugaku Takeda, Chelsea E. Ray, Zhenghong Dong, Mathieu Berge, A. Ari Hakimi, Sebastien Monette, Carl L. Lekaye, Jason A. Koutcher, Christina S. Leslie, Chad J. Creighton, Nils Weinhold, William Lee, Satish K. Tickoo, Zhong Wang, Emily H. Cheng, and James J. Hsieh
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kidney cancer ,ccRCC ,mouse tumor model ,VHL ,PBRM1 ,HIF1 ,STAT3 ,MTOR ,genetics ,epigenetics ,Biology (General) ,QH301-705.5 - Abstract
PBRM1 is the second most commonly mutated gene after VHL in clear cell renal cell carcinoma (ccRCC). However, the biological consequences of PBRM1 mutations for kidney tumorigenesis are unknown. Here, we find that kidney-specific deletion of Vhl and Pbrm1, but not either gene alone, results in bilateral, multifocal, transplantable clear cell kidney cancers. PBRM1 loss amplified the transcriptional outputs of HIF1 and STAT3 incurred by Vhl deficiency. Analysis of mouse and human ccRCC revealed convergence on mTOR activation, representing the third driver event after genetic inactivation of VHL and PBRM1. Our study reports a physiological preclinical ccRCC mouse model that recapitulates somatic mutations in human ccRCC and provides mechanistic and therapeutic insights into PBRM1 mutated subtypes of human ccRCC.
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- 2017
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6. Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets
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Ying-Bei Chen, Jianing Xu, Anders Jacobsen Skanderup, Yiyu Dong, A. Rose Brannon, Lu Wang, Helen H. Won, Patricia I. Wang, Gouri J. Nanjangud, Achim A. Jungbluth, Wei Li, Virginia Ojeda, A. Ari Hakimi, Martin H. Voss, Nikolaus Schultz, Robert J. Motzer, Paul Russo, Emily H. Cheng, Filippo G. Giancotti, William Lee, Michael F. Berger, Satish K. Tickoo, Victor E. Reuter, and James J. Hsieh
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Science - Abstract
A subset of renal cell carcinomas have uncertain histology and are aggressive in nature. Here, the authors examine this group of unclassified renal cancers using genomics techniques and identify further subclasses of the tumours that have differing prognoses.
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- 2016
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7. Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma
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Jianing Xu, Ed Reznik, Ho-Joon Lee, Gunes Gundem, Philip Jonsson, Judy Sarungbam, Anna Bialik, Francisco Sanchez-Vega, Chad J Creighton, Jake Hoekstra, Li Zhang, Peter Sajjakulnukit, Daniel Kremer, Zachary Tolstyka, Jozefina Casuscelli, Steve Stirdivant, Jie Tang, Nikolaus Schultz, Paul Jeng, Yiyu Dong, Wenjing Su, Emily H Cheng, Paul Russo, Jonathan A Coleman, Elli Papaemmanuil, Ying-Bei Chen, Victor E Reuter, Chris Sander, Scott R Kennedy, James J Hsieh, Costas A Lyssiotis, Satish K Tickoo, and A Ari Hakimi
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kidney cancer ,genomics ,metabolomics ,mitochondrial DNA ,sorbitol ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
While genomic sequencing routinely identifies oncogenic alterations for the majority of cancers, many tumors harbor no discernable driver lesion. Here, we describe the exceptional molecular phenotype of a genomically quiet kidney tumor, clear cell papillary renal cell carcinoma (CCPAP). In spite of a largely wild-type nuclear genome, CCPAP tumors exhibit severe depletion of mitochondrial DNA (mtDNA) and RNA and high levels of oxidative stress, reflecting a shift away from respiratory metabolism. Moreover, CCPAP tumors exhibit a distinct metabolic phenotype uniquely characterized by accumulation of the sugar alcohol sorbitol. Immunohistochemical staining of primary CCPAP tumor specimens recapitulates both the depletion of mtDNA-encoded proteins and a lipid-depleted metabolic phenotype, suggesting that the cytoplasmic clarity in CCPAP is primarily related to the presence of glycogen. These results argue for non-genetic profiling as a tool for the study of cancers of unknown driver.
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- 2019
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8. Figure S5 from Targeting the mTOR Pathway in Hurthle Cell Carcinoma Results in Potent Antitumor Activity
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Ian Ganly, Timothy A. Chan, Ronald Ghossein, Bin Xu, Eric J. Sherman, James A. Fagin, Rui Qu, Huiyong Zhao, Omer Aras, Gouri J. Nanjangud, Ed Reznik, Vladimir Makarov, Fengshen Kuo, Yongxing Gong, and Yiyu Dong
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Combination treatment with rapamycin and lenvatinib in PDX model TC1m1. A, Combination treatment resulted in enhanced decrease in CD31 staining endothelial vessels compared to lenvatinib alone or rapamycin alone. B, The average IMVD values of CD31 in tumors from mice treated with different drugs were decreased to 44.5% (rapamycin), 60.6% (lenvatinib), and 16.9% (combination of rapamycin and lenvatinib), respectively, compared with that in vehicle control group.
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- 2023
9. Supplementary Figures 1-4, Table 1 from Loss of Trop2 Promotes Carcinogenesis and Features of Epithelial to Mesenchymal Transition in Squamous Cell Carcinoma
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Loren S. Michel, Christine H. Chung, Jason D. Weber, Jeffrey M. Arbeit, Raleigh D. Kladney, James Lewis, Peter Humphrey, Ryan Day, Yiyu Dong, Aimin Li, Dorota Grabowska, Kaihua Zhang, and Jianbo Wang
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PDF file - 264K
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- 2023
10. Data from Loss of Trop2 Promotes Carcinogenesis and Features of Epithelial to Mesenchymal Transition in Squamous Cell Carcinoma
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Loren S. Michel, Christine H. Chung, Jason D. Weber, Jeffrey M. Arbeit, Raleigh D. Kladney, James Lewis, Peter Humphrey, Ryan Day, Yiyu Dong, Aimin Li, Dorota Grabowska, Kaihua Zhang, and Jianbo Wang
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Trop2, an oncogenic cell surface protein under investigation as a therapeutic target, is commonly overexpressed in several epithelial tumor types yet its function in tumor biology remains relatively unexplored. To investigate the role of Trop2 in epithelial carcinogenesis, we generated Trop2−/− mice, which are viable and possess a normal lifespan. Contrary to expectations, Trop2 loss fails to suppress keratinocyte transformation. Instead, ras-transformed Trop2−/− keratinocytes preferentially pass through an epithelial to mesenchymal transition (EMT) and form tumors with spindle cell histology. Furthermore, Trop2 loss renders Arf-null mice susceptible to the formation of biphasic sarcomatoid carcinomas containing both squamous and spindle cell components upon carcinogen exposure in an otherwise skin cancer–resistant strain (C57BL/6). Immortalized keratinocytes derived from Trop2−/−Arf−/− mice exhibit enhanced proliferative and migratory capacity as well as increased activation of mitogen-activated protein kinase and Src prior to transformation. The clinical relevance of these findings was supported by studying the molecular epidemiology of Trop2 in primary head and neck squamous cell carcinomas. This analysis revealed that Trop2 mRNA levels are decreased in a subset of tumors with features of EMT, and total loss of Trop2 protein expression is observed in the spindle cell component of sarcomatoid carcinomas. Therefore, while previous studies have emphasized the potential importance of Trop2 gain of function, these results uncover a role for Trop2 loss in tumorigenesis and the mesenchymal transdifferentiation observed in a subset of squamous cell carcinomas. Mol Cancer Res; 9(12); 1686–95. ©2011 AACR.
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- 2023
11. Table S1 from Targeting the mTOR Pathway in Hurthle Cell Carcinoma Results in Potent Antitumor Activity
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Ian Ganly, Timothy A. Chan, Ronald Ghossein, Bin Xu, Eric J. Sherman, James A. Fagin, Rui Qu, Huiyong Zhao, Omer Aras, Gouri J. Nanjangud, Ed Reznik, Vladimir Makarov, Fengshen Kuo, Yongxing Gong, and Yiyu Dong
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Quantitative RT-PCR primer sequences
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- 2023
12. Data from Targeting the mTOR Pathway in Hurthle Cell Carcinoma Results in Potent Antitumor Activity
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Ian Ganly, Timothy A. Chan, Ronald Ghossein, Bin Xu, Eric J. Sherman, James A. Fagin, Rui Qu, Huiyong Zhao, Omer Aras, Gouri J. Nanjangud, Ed Reznik, Vladimir Makarov, Fengshen Kuo, Yongxing Gong, and Yiyu Dong
- Abstract
Hurthle cell carcinomas (HCCs) are refractory to radioactive iodine and unresponsive to chemotherapeutic agents, with a fatality rate that is the highest among all types of thyroid cancer after anaplastic thyroid cancer. Our previous study on the genomic landscape of HCCs identified a high incidence of disruptions of mTOR pathway effectors. Here, we report a detailed analysis of mTOR signaling in cell line and patient-derived xenograft mouse models of HCCs. We show that mTOR signaling is upregulated and that targeting mTOR signaling using mTOR inhibitors suppresses tumor growth in primary tumors and distant metastasis. Mechanistically, ablation of mTOR signaling impaired the expression of p-S6 and cyclin A2, resulting in the decrease of the S phase and blocking of cancer cell proliferation. Strikingly, mTOR inhibitor treatment significantly reduced lung metastatic lesions, with the decreased expression of Snail in xenograft tumors. Our data demonstrate that mTOR pathway blockade represents a novel treatment strategy for HCC.
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- 2023
13. Bio-inspired Computation Approach for Tumor Growth with Spatial Randomness Analysis of Kidney Cancer Xenograft Pathology Slides.
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Aydin Saribudak, Yiyu Dong, James Hsieh, and M. ümit Uyar
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- 2015
14. Mathematical models of tumor growth using Voronoi tessellations in pathology slides of kidney cancer.
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Aydin Saribudak, Yiyu Dong, Stephen Gundry, James Hsieh, and M. ümit Uyar
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- 2015
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15. Supplementary Figure Legends 1-4 from Synthetic Lethality through Combined Notch–Epidermal Growth Factor Receptor Pathway Inhibition in Basal-Like Breast Cancer
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Loren S. Michel, Jason D. Weber, Jianbo Wang, Aimin Li, and Yiyu Dong
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Supplementary Figure Legends 1-4 from Synthetic Lethality through Combined Notch–Epidermal Growth Factor Receptor Pathway Inhibition in Basal-Like Breast Cancer
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- 2023
16. Supplementary Figure 3 from Synthetic Lethality through Combined Notch–Epidermal Growth Factor Receptor Pathway Inhibition in Basal-Like Breast Cancer
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Loren S. Michel, Jason D. Weber, Jianbo Wang, Aimin Li, and Yiyu Dong
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Supplementary Figure 3 from Synthetic Lethality through Combined Notch–Epidermal Growth Factor Receptor Pathway Inhibition in Basal-Like Breast Cancer
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- 2023
17. Data from Synthetic Lethality through Combined Notch–Epidermal Growth Factor Receptor Pathway Inhibition in Basal-Like Breast Cancer
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Loren S. Michel, Jason D. Weber, Jianbo Wang, Aimin Li, and Yiyu Dong
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Basal-like breast cancers (BLBC) are highly aggressive, yet selective therapies targeting the specific oncoproteins driving these tumors have not been developed. These cancers frequently express epidermal growth factor receptor (EGFR), with resistance to its inhibition being well documented, albeit poorly understood. Notch pathway activation is also common in this breast cancer subtype and can be suppressed by γ-secretase inhibitors, which effectively block receptor cleavage and activation. Herein, we show that although inhibition of either EGFR or Notch signaling alone is insufficient to suppress basal-like breast tumor cell survival and proliferation, simultaneous inhibition uncovers a synthetic lethal relationship between these two oncogenic pathways. This lethality is due in part to significant decreases in AKT activation caused by combined EGFR and Notch inhibition. Expression of the activated form of Notch1 restores AKT activity and enables cells to overcome cell death after dual-pathway blockade. Combined pathway inhibition is also dramatically more effective at suppressing tumor growth in mice than blocking EGFR or Notch signaling alone. Thus, we show that Notch pathway activation contributes to resistance to EGFR inhibition, and provide a novel treatment strategy for BLBCs. Cancer Res; 70(13); 5465–74. ©2010 AACR.
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- 2023
18. Supplementary Figure 4 from Synthetic Lethality through Combined Notch–Epidermal Growth Factor Receptor Pathway Inhibition in Basal-Like Breast Cancer
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Loren S. Michel, Jason D. Weber, Jianbo Wang, Aimin Li, and Yiyu Dong
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Supplementary Figure 4 from Synthetic Lethality through Combined Notch–Epidermal Growth Factor Receptor Pathway Inhibition in Basal-Like Breast Cancer
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- 2023
19. Supplementary Figure 2 from Synthetic Lethality through Combined Notch–Epidermal Growth Factor Receptor Pathway Inhibition in Basal-Like Breast Cancer
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Loren S. Michel, Jason D. Weber, Jianbo Wang, Aimin Li, and Yiyu Dong
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Supplementary Figure 2 from Synthetic Lethality through Combined Notch–Epidermal Growth Factor Receptor Pathway Inhibition in Basal-Like Breast Cancer
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- 2023
20. Supplementary Methods, Figures 1-7, Tables 1-3 from A Pharmacologic Inhibitor of the Protease Taspase1 Effectively Inhibits Breast and Brain Tumor Growth
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James J.-D. Hsieh, Emily H.-Y. Cheng, Robert H. Shoemaker, Richard Gussio, Ann Hermone, Stanley J. Korsmeyer, Kyoung J. Oh, David R. Piwnica-Worms, Yiyu Dong, Shugaku Takeda, Ho-Chou Tu, Han Liu, Todd D. Westergard, Adam C. Searleman, Brian A. Van Tine, Yishan Lee, and David Y. Chen
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PDF file - 782K
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- 2023
21. Supplementary Figure 1 from Synthetic Lethality through Combined Notch–Epidermal Growth Factor Receptor Pathway Inhibition in Basal-Like Breast Cancer
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Loren S. Michel, Jason D. Weber, Jianbo Wang, Aimin Li, and Yiyu Dong
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Supplementary Figure 1 from Synthetic Lethality through Combined Notch–Epidermal Growth Factor Receptor Pathway Inhibition in Basal-Like Breast Cancer
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- 2023
22. Mitonuclear genotype remodels the metabolic and microenvironmental landscape of Hürthle cell carcinoma
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Ian Ganly, Eric Minwei Liu, Fengshen Kuo, Vladimir Makarov, Yiyu Dong, Jinsung Park, Yongxing Gong, Alexander N. Gorelick, Jeffrey A Knauf, Elisa Benedetti, Jacqueline Tait-Mulder, Luc G.T. Morris, James A. Fagin, Andrew M Intlekofer, Jan Krumsiek, Payam A. Gammage, Ronald Ghossein, Bin Xu, Timothy A. Chan, and Ed Reznik
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Carcinoma, Hepatocellular ,Oxyphil Cells ,Multidisciplinary ,Genotype ,Liver Neoplasms ,Mutation ,Tumor Microenvironment ,Humans ,Thyroid Neoplasms ,DNA, Mitochondrial - Abstract
Hürthle cell carcinomas (HCCs) display two exceptional genotypes: near-homoplasmic mutation of mitochondrial DNA (mtDNA) and genome-wide loss of heterozygosity (gLOH). To understand the phenotypic consequences of these genetic alterations, we analyzed genomic, metabolomic, and immunophenotypic data of HCC and other thyroid cancers. Both mtDNA mutations and profound depletion of citrate pools are common in HCC and other thyroid malignancies, suggesting that thyroid cancers are broadly equipped to survive tricarboxylic acid cycle impairment, whereas metabolites in the reduced form of NADH-dependent lysine degradation pathway were elevated exclusively in HCC. The presence of gLOH was not associated with metabolic phenotypes but rather with reduced immune infiltration, indicating that gLOH confers a selective advantage partially through immunosuppression. Unsupervised multimodal clustering revealed four clusters of HCC with distinct clinical, metabolomic, and microenvironmental phenotypes but overlapping genotypes. These findings chart the metabolic and microenvironmental landscape of HCC and shed light on the interaction between genotype, metabolism, and the microenvironment in cancer.
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- 2022
23. Persistent Severe Hyperlactatemia and Metabolic Derangement in Lethal
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Chung-Han, Lee, Gunes, Gundem, William, Lee, Ying-Bei, Chen, Justin R, Cross, Yiyu, Dong, Almedina, Redzematovic, Roy, Mano, Elizabeth Y, Wei, Emily H, Cheng, Ramaprasad, Srinivasan, Dayna, Oschwald, A Ari, Hakimi, Mark P, Dunphy, W Marston, Linehan, Elli, Papaemmanuil, and James J, Hsieh
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To describe the unique clinical features, determine the genomics, and investigate the metabolic derangement of an extremely rare form of a hereditary lethal kidney cancer syndrome.Three patients with lethal kidney cancer (age 19, 20, and 37 years) exhibiting persistent (1 to 3 months) extremely high levels of blood lactate (5 mM) despite normal oxygen perfusion, highly avid tumors on [All three patients with kidney cancer were initially given various diagnoses as a result of diverse tumor histopathology and atypical clinical presentations. The correct diagnoses of theseSDHB-deficient metastatic renal cell carcinoma is a rare, aggressive form of kidney cancer that manifests with clinical evidence of a severe Warburg effect, and genomic studies demonstrated two genetic hits at
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- 2022
24. Targeting the mTOR Pathway in Hurthle Cell Carcinoma Results in Potent Anti-Tumor Activity
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Bin Xu, Fengshen Kuo, Eric J. Sherman, James A. Fagin, Yongxing Gong, Ian Ganly, Timothy A. Chan, Omer Aras, Yiyu Dong, HuiYong Zhao, Ed Reznik, Ronald Ghossein, Vladimir Makarov, Rui Qu, and Gouri Nanjangud
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Male ,Cancer Research ,Cell ,Mice, SCID ,Article ,Mice ,Downregulation and upregulation ,Cell Line, Tumor ,Neoplasms ,medicine ,Adenoma, Oxyphilic ,Animals ,Humans ,Thyroid Neoplasms ,Anaplastic thyroid cancer ,Thyroid cancer ,PI3K/AKT/mTOR pathway ,business.industry ,TOR Serine-Threonine Kinases ,HCCS ,medicine.disease ,Blockade ,Disease Models, Animal ,medicine.anatomical_structure ,Oncology ,Cancer research ,business ,Cyclin A2 - Abstract
Hurthle cell carcinomas (HCCs) are refractory to radioactive iodine and unresponsive to chemotherapeutic agents, with a fatality rate that is the highest among all types of thyroid cancer after anaplastic thyroid cancer. Our previous study on the genomic landscape of HCCs identified a high incidence of disruptions of mTOR pathway effectors. Here, we report a detailed analysis of mTOR signaling in cell line and patient-derived xenograft mouse models of HCCs. We show that mTOR signaling is upregulated and that targeting mTOR signaling using mTOR inhibitors suppresses tumor growth in primary tumors and distant metastasis. Mechanistically, ablation of mTOR signaling impaired the expression of p-S6 and cyclin A2, resulting in the decrease of the S phase and blocking of cancer cell proliferation. Strikingly, mTOR inhibitor treatment significantly reduced lung metastatic lesions, with the decreased expression of Snail in xenograft tumors. Our data demonstrate that mTOR pathway blockade represents a novel treatment strategy for HCC.
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- 2021
25. Hyperpolarized MRI Visualizes Warburg Effects and Predicts Treatment Response to mTOR Inhibitors in Patient-Derived ccRCC Xenograft Models
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Chelsea E. Ray, Kayvan R. Keshari, Sangmoo Jeong, Sui Seng Tee, Yiyu Dong, Vesselin Z. Miloushev, Ying-Bei Chen, Kristin L. Granlund, Roozbeh Eskandari, Omer Aras, Emily H. Cheng, James J. Hsieh, and Lidia Dos Santos-Cunha
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Metastasis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Renal cell carcinoma ,Internal medicine ,Pyruvic Acid ,Image Processing, Computer-Assisted ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Carcinoma, Renal Cell ,PI3K/AKT/mTOR pathway ,Sirolimus ,Tumor microenvironment ,Antibiotics, Antineoplastic ,Everolimus ,business.industry ,TOR Serine-Threonine Kinases ,medicine.disease ,Magnetic Resonance Imaging ,Xenograft Model Antitumor Assays ,Kidney Neoplasms ,Temsirolimus ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,business ,Kidney cancer ,medicine.drug - Abstract
The ever-changing tumor microenvironment constantly challenges individual cancer cells to balance supply and demand, presenting tumor vulnerabilities and therapeutic opportunities. Everolimus and temsirolimus are inhibitors of mTOR (mTORi) approved for treating metastatic renal cell carcinoma (mRCC). However, treatment outcome varies greatly among patients. Accordingly, administration of mTORi in mRCC is diminishing, which could potentially result in missing timely delivery of effective treatment for select patients. Here, we implemented a clinically applicable, integrated platform encompassing a single dose of [1-13C] pyruvate to visualize the in vivo effect of mTORi on the conversion of pyruvate to lactate using hyperpolarized MRI. A striking difference that predicts treatment benefit was demonstrated using two preclinical models derived from patients with clear cell RCC (ccRCC) who exhibited primary resistance to VEGFRi and quickly succumbed to their diseases within 6 months after the diagnosis of metastasis without receiving mTORi. Our findings suggest that hyperpolarized MRI could be further developed to personalize kidney cancer treatment. Significance: These findings demonstrate hyperpolarized [1-13C]pyruvate MRI as a tool for accurately assessing the clinical success of mTOR inhibition in patients with ccRCC.
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- 2019
26. Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts
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Katie S. Murray, Jonathan A. Coleman, Nima Almassi, Benjamin R. Gordon, Aphrothiti J. Hanrahan, Arijh Elzein, Irit Sagi, Vishnu Mohan, Ziyu Chen, Karan Nagar, Ricardo Alvim, Wenhuo Hu, Emiliano Cocco, François Audenet, Alessandro D. Santin, David B. Solit, Sylvia Jebiwott, Alex Penson, Aditya Bagrodia, Maurizio Scaltriti, Gopa Iyer, Nathan D. Wong, Jonathan E. Rosenberg, Kwanghee Kim, Eugene J. Pietzak, Hikmat Al-Ahmadie, A. Ari Hakimi, H. A. Vargas, Christopher C.W. Hughes, James J. Hsieh, Yiyu Dong, Shawn Dason, Timothy Clinton, Philip A. Watson, Jianjiong Gao, Irina Ostrovnaya, and Sizhi P. Gao
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Male ,0301 basic medicine ,Antibody-drug conjugate ,Science ,Urology ,Concordance ,Urinary Bladder ,General Physics and Astronomy ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Urethra ,Carcinoma ,medicine ,Humans ,lcsh:Science ,Cancer ,Urethral Neoplasms ,Multidisciplinary ,Bladder cancer ,business.industry ,General Chemistry ,medicine.disease ,Precision medicine ,3. Good health ,Gene expression profiling ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Monoclonal ,Cancer research ,lcsh:Q ,Personalized medicine ,business ,Penis - Abstract
Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients., The advancement of upper tract urothelial carcinoma (UTUC) research is hampered by the lack of disease-specific models. Here, the authors report patient derived xenograft and cell line models of UTUC, and show that these models retain the genomic and biological heterogeneity of human disease.
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- 2020
27. Molecular characterization of sarcomatoid clear cell renal cell carcinoma unveils new candidate oncogenic drivers
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Nizar M. Tannir, Yiyu Dong, Ronan Flippot, Xiaoping Su, Morgan Rouprêt, Jose A. Karam, Paul Russo, Eva Compérat, Gabriel G. Malouf, James J. Hsieh, Satish K. Tickoo, Ying-Bei Chen, Renzo G. DiNatale, Hui Yao, A. Ari Hakimi, Roger Mouawad, Jean Philippe Spano, Roy Mano, Kyle A. Blum, David Khayat, Thai H. Ho, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Strasbourg, Institut de Cancérologie de Strasbourg Europe (ICANS), Memorial Sloan Kettering Cancer Center (MSKCC), The University of Texas M.D. Anderson Cancer Center [Houston], CHU Tenon [AP-HP], Sorbonne Université (SU), Epidémiologie, Systèmes d'Information, Modélisation, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), MD Anderson Cancer Center [Houston], The University of Texas Health Science Center at Houston (UTHealth), Mayo Clinic [Scottsdale], Mayo Clinic, Mayo Clinic [Rochester], Washington University in Saint Louis (WUSTL), and univOAK, Archive ouverte
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Male ,Cell ,Gene regulatory network ,lcsh:Medicine ,Mice ,0302 clinical medicine ,Gene Regulatory Networks ,lcsh:Science ,Cancer genetics ,Cancer ,Laser capture microdissection ,YAP1 ,Neurofibromin 2 ,0303 health sciences ,Multidisciplinary ,Kidney Neoplasms ,Up-Regulation ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Signal Transduction ,animal structures ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Laser Capture Microdissection ,Protein Serine-Threonine Kinases ,Biology ,Article ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,medicine ,Carcinoma ,Animals ,Humans ,Genetic Predisposition to Disease ,Hippo Signaling Pathway ,Carcinoma, Renal Cell ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,030304 developmental biology ,Cell Nucleus ,Hippo signaling pathway ,Cell growth ,lcsh:R ,YAP-Signaling Proteins ,Sequence Analysis, DNA ,medicine.disease ,Clear cell renal cell carcinoma ,Transcriptional Coactivator with PDZ-Binding Motif Proteins ,Mutation ,Trans-Activators ,Cancer research ,lcsh:Q ,Neoplasm Transplantation ,Transcription Factors - Abstract
Sarcomatoid clear-cell renal cell carcinomas (sRCC) are associated with dismal prognosis. Genomic alterations associated with sarcomatoid dedifferentiation are poorly characterized. We sought to define the genomic landscape of sRCC and uncover potentially actionable therapeutic targets. We assessed the genomic landscape of sRCC using targeted panel sequencing including patients with microdissected sarcomatoid and epithelial components. Along with common genomic alterations associated with clear-cell histology, we found that Hippo was one of the most frequently altered pathways in these tumours. Hippo alterations were differentially enriched in sRCC compared to non-sRCC. Functional analysis showed that Hippo members mutations were associated with higher nuclear accumulation of YAP/TAZ, core effectors of the Hippo pathway. In a NF2-mutant sRCC model, YAP1 knockdown and NF2 reconstitution suppressed cell proliferation, tumour growth and invasion, both in vitro and in vivo. Overall, we show that Hippo pathway alterations are a feature of sRCC, and enable the exploration of the Hippo pathway as a novel potential therapeutic target.
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- 2020
28. Tumor Xenografts of Human Clear Cell Renal Cell Carcinoma But Not Corresponding Cell Lines Recapitulate Clinical Response to Sunitinib: Feasibility of Using Biopsy Samples
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Song Han, Nicole Benfante, Martin H. Voss, Chung-Han Lee, Jeremy C. Durack, Maria F. Becerra, Maria E. Arcila, John H. Healey, James J. Hsieh, Mohit Chawla, Brandon J. Manley, Nicola Fabbri, Yiyu Dong, A. Ari Hakimi, Omer Aras, Robert J. Motzer, Patrick J. Boland, Almedina Redzematovic, Jozefina Casuscelli, Jonathan A. Coleman, Ying-Bei Chen, Ed Reznik, Daniel M. Tennenbaum, Emily H. Cheng, Darren R. Feldman, and Paul Russo
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Pathology ,Urology ,medicine.medical_treatment ,Transplantation, Heterologous ,Antineoplastic Agents ,Mice, SCID ,Kidney ,Article ,Targeted therapy ,Random Allocation ,03 medical and health sciences ,0302 clinical medicine ,Mice, Inbred NOD ,Renal cell carcinoma ,Cell Line, Tumor ,Biopsy ,Sunitinib ,medicine ,Animals ,Humans ,Carcinoma, Renal Cell ,Aged ,medicine.diagnostic_test ,business.industry ,Biopsy, Needle ,Histology ,Middle Aged ,medicine.disease ,Xenograft Model Antitumor Assays ,Kidney Neoplasms ,Clear cell renal cell carcinoma ,Treatment Outcome ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Feasibility Studies ,Heterografts ,Female ,Histopathology ,business ,Clear cell ,medicine.drug - Abstract
Background Parallel development of preclinical models that recapitulate treatment response observed in patients is central to the advancement of personalized medicine. Objective To evaluate the use of biopsy specimens to develop patient-derived xenografts and the use of corresponding cell lines from renal cell carcinoma (RCC) tumors for the assessment of histopathology, genomics, and treatment response. Design, setting, and participants A total of 74 tumor specimens from 66 patients with RCC were implanted into immunocompromised NOD- SCID IL2Rg −/− mice. Four cell lines generated from patients' specimens with clear cell pathology were used for comparative studies. Outcome measurements and statistical analysis Preclinical models were established and assessed. Engraftment rates were analyzed using chi-square testing. Analysis of variance (two-way analysis of variance) was conducted to assess tumor growth. Results and limitations Overall, 33 RCC mouse xenograft models were generated with an overall engraftment rate of 45% (33 of 74). Tumor biopsies engrafted comparably with surgically resected tumors (58% vs 41%; p =0.3). Xenograft tumors and their original tumors showed high fidelity in regard to histology, mutation status, copy number change, and targeted therapy response. Engraftment rates from metastatic tumors were higher but not more significant than primary tumors (54% vs 34%; p =0.091). Our engraftment rate using metastases or biopsies was comparable with recent reports using resected primary tumors. In stark contrast to corresponding cell lines, all tested xenografts recapitulated patients' clinical response to sunitinib. Conclusions Patient-derived xenograft models can be effectively established from tumor biopsies. Preclinical xenograft models but not matched cell lines reflected clinical responses to sunitinib. Patient summary Matched patient-derived clear cell renal cell carcinoma xenografts and cell lines from responsive and refractory patients treated with sunitinib were established and evaluated for pharmacologic response to anti–vascular endothelial growth factor treatment. Both models accurately reflected the genetic characteristics of original tumors, but only xenografts recapitulated drug responses observed in patients. These models could serve as a powerful platform for precision medicine.
- Published
- 2017
29. ΔNp63 Inhibits Oxidative Stress-Induced Cell Death, Including Ferroptosis, and Cooperates with the BCL-2 Family to Promote Clonogenic Survival
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Yiyu Dong, Yufeng Wang, Song Han, Han Liu, Shugaku Takeda, Gary X. Wang, Emily H. Cheng, James J. Hsieh, Ho-Chou Tu, Anders Jacobsen Skanderup, and Yogesh Tengarai Ganesan
- Subjects
0301 basic medicine ,Programmed cell death ,DNA damage ,Apoptosis ,medicine.disease_cause ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Transcriptional regulation ,medicine ,Animals ,Anoikis ,lcsh:QH301-705.5 ,Cell Death ,Tumor Suppressor Proteins ,Bcl-2 family ,Glutathione ,Flow Cytometry ,3. Good health ,Oxidative Stress ,030104 developmental biology ,Proto-Oncogene Proteins c-bcl-2 ,lcsh:Biology (General) ,chemistry ,Cancer research ,Reactive Oxygen Species ,Oxidative stress - Abstract
Summary: The BCL-2 family proteins are central regulators of apoptosis. However, cells deficient for BAX and BAK or overexpressing BCL-2 still succumb to oxidative stress upon DNA damage or matrix detachment. Here, we show that ΔNp63α overexpression protects cells from oxidative stress induced by oxidants, DNA damage, anoikis, or ferroptosis-inducing agents. Conversely, ΔNp63α deficiency increases oxidative stress. Mechanistically, ΔNp63α orchestrates redox homeostasis through transcriptional control of glutathione biogenesis, utilization, and regeneration. Analysis of a lung squamous cell carcinoma dataset from The Cancer Genome Atlas (TCGA) reveals that TP63 amplification/overexpression upregulates the glutathione metabolism pathway in primary human tumors. Strikingly, overexpression of ΔNp63α promotes clonogenic survival of p53−/−Bax−/−Bak−/− cells against DNA damage. Furthermore, co-expression of BCL-2 and ΔNp63α confers clonogenic survival against matrix detachment, disrupts the luminal clearance of mammary acini, and promotes cancer metastasis. Our findings highlight the need for a simultaneous blockade of apoptosis and oxidative stress to promote long-term cellular well-being. : Apoptosis-defective cells remain vulnerable to oxidative stress, which limits long-term survival. Wang et al. identify ΔNp63α as a central regulator of redox homeostasis through transcriptional control of a tightly coupled glutathione metabolic circuit. ΔNp63α alleviates oxidative stress and cooperates with the BCL-2 family to promote both long-term cellular well-being and cancer metastasis. Keywords: oxidative stress, ROS, apoptosis, necrosis, programmed necrotic death, TP63, BCL-2, ferroptosis, redox, glutathione metabolism
- Published
- 2017
30. Persistent Severe Hyperlactatemia and Metabolic Derangement in Lethal SDHB-Mutated Metastatic Kidney Cancer: Clinical Challenges and Examples of Extreme Warburg Effect
- Author
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Almedina Redzematovic, Dayna M. Oschwald, Mark Dunphy, Chung-Han Lee, Ying-Bei Chen, Gunes Gundem, A. Ari Hakimi, Elizabeth Y. Wei, James J. Hsieh, Justin R. Cross, William Lee, Yiyu Dong, Roy Mano, Elli Papaemmanuil, W. Marston Linehan, Ramaprasad Srinivasan, and Emily H. Cheng
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Pathology ,SDHB ,business.industry ,Cell ,medicine.disease ,Warburg effect ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,medicine ,Immunohistochemistry ,Histopathology ,Hyperlactatemia ,business ,Perfusion ,Kidney cancer - Abstract
Purpose To describe the unique clinical features, determine the genomics, and investigate the metabolic derangement of an extremely rare form of a hereditary lethal kidney cancer syndrome. Patients and Methods Three patients with lethal kidney cancer (age 19, 20, and 37 years) exhibiting persistent (1 to 3 months) extremely high levels of blood lactate (> 5 mM) despite normal oxygen perfusion, highly avid tumors on [18F]fluorodeoxyglucose positron emission tomography (PET), and pleomorphic histopathologic features were identified and treated in a single institute. Integrated studies including whole-genome sequencing (WGS), targeted sequencing, immunohistochemistry, cell-based assays, and 18F-glutamine PET imaging were performed to investigate this rare kidney cancer syndrome. Results All three patients with kidney cancer were initially given various diagnoses as a result of diverse tumor histopathology and atypical clinical presentations. The correct diagnoses of these SDHB-mutated renal cell carcinomas were first made based on cancer genomics. Genomic studies of the blood and tumors of these patients identified three different kinds of germline loss-of-function mutations in the SDHB gene and the common loss of heterozygosity in the remaining SDHB allele thorough somatic chromosome 1p deletion. In one patient, WGS revealed that a germline mutation of SDHB coupled with loss of heterozygosity was the sole genetic event. Cancer evolution analysis of SDHB tumors based on WGS demonstrated that SDHB in kidney epithelium fulfills the Knudson two-hit criteria as a major tumor suppressor gene. SDHB−/− tumor cells displayed increase in glucose uptake and lactate production, alteration in mitochondrial architecture, and defect in oxidative respiration. 18F-Glutamine PET imaging studies demonstrated increased glutamine metabolism. Conclusion SDHB-deficient metastatic renal cell carcinoma is a rare, aggressive form of kidney cancer that manifests with clinical evidence of a severe Warburg effect, and genomic studies demonstrated two genetic hits at SDHB genes during kidney tumorigenesis.
- Published
- 2017
31. The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma
- Author
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Christina S. Leslie, Mathieu Berge, Toshinao Oyama, A. Ari Hakimi, Patricia Wang, Song Han, Hatice U. Osmangeyoglu, Amrita M. Nargund, Zhenghong Dong, Emily H. Cheng, Chad J. Creighton, James J. Hsieh, Yiyu Dong, Omer Aras, Yuchen Xie, Shugaku Takeda, Nils Weinhold, Satish K. Tickoo, Can G. Pham, Carl Lekaye, Jason A. Koutcher, Zhong Wang, Chelsea E. Ray, William Lee, and Sebastien Monette
- Subjects
0301 basic medicine ,Transcription, Genetic ,Somatic cell ,Hydronephrosis ,Kidney ,medicine.disease_cause ,Oxidative Phosphorylation ,PBRM1 ,STAT3 ,Mice ,genetics ,lcsh:QH301-705.5 ,MTOR ,Nuclear Proteins ,kidney cancer ,Kidney Neoplasms ,SWI/SNF ,3. Good health ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Von Hippel-Lindau Tumor Suppressor Protein ,Signal Transduction ,STAT3 Transcription Factor ,HIF1 ,Down-Regulation ,mouse tumor model ,Mechanistic Target of Rapamycin Complex 1 ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,HMGB Proteins ,VHL ,medicine ,Animals ,Humans ,Epigenetics ,Carcinoma, Renal Cell ,PI3K/AKT/mTOR pathway ,Integrases ,epigenetics ,Gene Expression Profiling ,ccRCC ,Hypoxia-Inducible Factor 1, alpha Subunit ,medicine.disease ,Clear cell renal cell carcinoma ,030104 developmental biology ,lcsh:Biology (General) ,Cancer research ,Carcinogenesis ,Gene Deletion ,Clear cell ,Transcription Factors - Abstract
PBRM1 is the second most commonly mutated gene after VHL in clear cell renal cell carcinoma (ccRCC). However, the biological consequences of PBRM1 mutations for kidney tumorigenesis are unknown. Here, we find that kidney-specific deletion of Vhl and Pbrm1, but not either gene alone, results in bilateral, multifocal, transplantable clear cell kidney cancers. PBRM1 loss amplified the transcriptional outputs of HIF1 and STAT3 incurred by Vhl deficiency. Analysis of mouse and human ccRCC revealed convergence on mTOR activation, representing the third driver event after genetic inactivation of VHL and PBRM1. Our study reports a physiological preclinical ccRCC mouse model that recapitulates somatic mutations in human ccRCC and provides mechanistic and therapeutic insights into PBRM1 mutated subtypes of human ccRCC.
- Published
- 2017
32. Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets
- Author
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Michael F. Berger, Satish K. Tickoo, Anders Jacobsen Skanderup, Filippo G. Giancotti, Paul Russo, Helen Won, Nikolaus Schultz, Jianing Xu, Lu Wang, Yiyu Dong, Gouri Nanjangud, A. Rose Brannon, A. Ari Hakimi, Virginia Ojeda, Wei Li, William Lee, Achim A. Jungbluth, Patricia Wang, James J. Hsieh, Ying-Bei Chen, Emily H. Cheng, Victor E. Reuter, Robert J. Motzer, and Martin H. Voss
- Subjects
0301 basic medicine ,Neurofibromatosis 2 ,Somatic cell ,Science ,General Physics and Astronomy ,Biology ,urologic and male genital diseases ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,SETD2 ,Renal cell carcinoma ,Cell Line, Tumor ,medicine ,PTEN ,Humans ,Carcinoma, Renal Cell ,PI3K/AKT/mTOR pathway ,In Situ Hybridization, Fluorescence ,BAP1 ,Multidisciplinary ,medicine.diagnostic_test ,TOR Serine-Threonine Kinases ,Tumor Suppressor Proteins ,General Chemistry ,Histone-Lysine N-Methyltransferase ,medicine.disease ,Kidney Neoplasms ,3. Good health ,Neoplasm Proteins ,030104 developmental biology ,HEK293 Cells ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Cancer research ,Immunohistochemistry ,Ubiquitin Thiolesterase ,Fluorescence in situ hybridization ,DNA Damage ,Signal Transduction - Abstract
Renal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell renal cell carcinomas that have no standard therapy. The oncogenic drivers in these tumours are unknown. Here we perform a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, single-nucleotide polymorphism array, fluorescence in situ hybridization, immunohistochemistry and cell-based assays. We identify recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%) and MTOR (8%). Integrated analysis reveals a subset of 26% uRCC characterized by NF2 loss, dysregulated Hippo–YAP pathway and worse survival, whereas 21% uRCC with mutations of MTOR, TSC1, TSC2 or PTEN and hyperactive mTORC1 signalling are associated with better clinical outcome. FH deficiency (6%), chromatin/DNA damage regulator mutations (21%) and ALK translocation (2%) distinguish additional cases. Altogether, this study reveals distinct molecular subsets for 76% of our uRCC cohort, which could have diagnostic and therapeutic implications., A subset of renal cell carcinomas have uncertain histology and are aggressive in nature. Here, the authors examine this group of unclassified renal cancers using genomics techniques and identify further subclasses of the tumours that have differing prognoses.
- Published
- 2016
33. A dual-modal PET/near infrared fluorescent nanotag for long-term immune cell tracking
- Author
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Naga Vara Kishore Pillarsetty, Mezruh Turkekul, Yiyu Dong, Stefan Harmsen, Richard Ting, Jose Lobo, Emin Ilker Medine, Omer Aras, Maxim A. Moroz, Oguz Akin, Fuad Nurili, and Vladimir Ponomarev
- Subjects
Biodistribution ,Adoptive cell transfer ,Biophysics ,Bioengineering ,02 engineering and technology ,Immunotherapy, Adoptive ,Article ,Biomaterials ,03 medical and health sciences ,Immune system ,Cell Line, Tumor ,medicine ,Cytotoxic T cell ,Humans ,Tissue Distribution ,Viability assay ,030304 developmental biology ,0303 health sciences ,Chemistry ,Cancer ,021001 nanoscience & nanotechnology ,medicine.disease ,Imaging agent ,Chimeric antigen receptor ,Mechanics of Materials ,Cell Tracking ,Positron-Emission Tomography ,Ceramics and Composites ,Cancer research ,0210 nano-technology - Abstract
Adoptive cell transfer of targeted chimeric antigen receptor (CAR) T cells has emerged as a highly promising cancer therapy. The pharmacodynamic action or CAR T cells is closely related to their pharmacokinetic profile; because of this as well as the risk of non-specific action, it is important to monitor their biodistribution and fate following infusion. To this end, we developed a dual-modal PET/near infrared fluorescent (NIRF) nanoparticle-based imaging agent for non-genomic labeling of human CAR T cells. Since the PET/NIRF nanoparticles did not affect cell viability or cytotoxic functionality and enabled long-term whole-body CAR T cell tracking using PET and NIRF in an ovarian peritoneal carcinomatosis model, this platform is a viable imaging technology to be applied in other cancer models.
- Published
- 2019
34. Author response: Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma
- Author
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Scott R. Kennedy, Wenjing Su, Anna Bialik, Yiyu Dong, Gunes Gundem, Paul S Jeng, Steve Stirdivant, Ying-Bei Chen, A. Ari Hakimi, Ed Reznik, James J. Hsieh, Zachary P. Tolstyka, Jonathan A. Coleman, Jake G. Hoekstra, Philip Jonsson, Jie Tang, Jianing Xu, Francisco Sanchez-Vega, Li Zhang, Satish K. Tickoo, Chad J. Creighton, Elli Papaemmanuil, Daniel M. Kremer, Ho-Joon Lee, Costas A. Lyssiotis, Chris Sander, Paul Russo, Jozefina Casuscelli, Victor E. Reuter, Peter Sajjakulnukit, Judy Sarungbam, Nikolaus Schultz, and Emily H. Cheng
- Subjects
Oxidative metabolism ,business.industry ,Cancer research ,Medicine ,business ,Clear cell papillary renal cell carcinoma ,medicine.disease - Published
- 2019
35. Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma
- Author
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Yiyu Dong, Nikolaus Schultz, Ying-Bei Chen, Jonathan A. Coleman, Jianing Xu, Jake G. Hoekstra, Emily H. Cheng, Chris Sander, Li Zhang, Elli Papaemmanuil, James J. Hsieh, Jozefina Casuscelli, Daniel M. Kremer, Eduard Reznik, Ho-Joon Lee, Steve Stirdivant, Francisco Sanchez-Vega, Wenjing Su, Paul S Jeng, A. Ari Hakimi, Chad J. Creighton, Anna Bialik, Scott R. Kennedy, Victor E. Reuter, Judy Sarungbam, Peter Sajjakulnukit, Satish K. Tickoo, Philip Jonsson, Jie Tang, Costas A. Lyssiotis, Zachary P. Tolstyka, Paul Russo, and Gunes Gundem
- Subjects
0301 basic medicine ,Mitochondrial DNA ,QH301-705.5 ,Science ,Cell Respiration ,mitochondrial DNA ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Lesion ,03 medical and health sciences ,0302 clinical medicine ,medicine ,genomics ,sorbitol ,Humans ,Biology (General) ,Carcinoma, Renal Cell ,General Immunology and Microbiology ,Histocytochemistry ,General Neuroscience ,RNA ,kidney cancer ,General Medicine ,Clear cell papillary renal cell carcinoma ,medicine.disease ,Immunohistochemistry ,metabolomics ,Aerobiosis ,Kidney Neoplasms ,3. Good health ,030104 developmental biology ,Cytoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,medicine.symptom ,Kidney cancer ,Oxidation-Reduction ,Oxidative stress ,Metabolic Networks and Pathways - Abstract
While genomic sequencing routinely identifies oncogenic alterations for the majority of cancers, many tumors harbor no discernable driver lesion. Here, we describe the exceptional molecular phenotype of a genomically quiet kidney tumor, clear cell papillary renal cell carcinoma (CCPAP). In spite of a largely wild-type nuclear genome, CCPAP tumors exhibit severe depletion of mitochondrial DNA (mtDNA) and RNA and high levels of oxidative stress, reflecting a shift away from respiratory metabolism. Moreover, CCPAP tumors exhibit a distinct metabolic phenotype uniquely characterized by accumulation of the sugar alcohol sorbitol. Immunohistochemical staining of primary CCPAP tumor specimens recapitulates both the depletion of mtDNA-encoded proteins and a lipid-depleted metabolic phenotype, suggesting that the cytoplasmic clarity in CCPAP is primarily related to the presence of glycogen. These results argue for non-genetic profiling as a tool for the study of cancers of unknown driver.
- Published
- 2019
36. Modeling Tumor Growth for Kidney Cancer Based on Nuclei Clusters of Pathology Slides
- Author
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Aydin Saribudak, Yiyu Dong, James Hsieh, and M. Umit Uyar
- Published
- 2016
37. Integrated genomic analysis of Hürthle cell cancer reveals oncogenic drivers, recurrent mitochondrial mutations, and unique chromosomal landscapes
- Author
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Luc G. T. Morris, Yiyu Dong, Ronald Ghossein, Ian Ganly, Kepal N. Patel, Shyamprasad Vasudeva Deraje, Pedro Blecua Carrillo Albornoz, Timothy A. Chan, Nadeem Riaz, Gouri Nanjangud, Martha A. Zeiger, Vladimir Makarov, Stephanie Eng, James A. Fagin, Electron Kebebew, Christopher B. Umbricht, Eric J. Sherman, Promita Bose, Yuri E. Nikiforov, Venkatraman E. Seshan, Ed Reznik, Iñigo Landa, and Fengshen Kuo
- Subjects
0301 basic medicine ,Cancer Research ,Mitochondrial DNA ,DNA Repair ,Loss of Heterozygosity ,Genomics ,Biology ,Haploidy ,DNA, Mitochondrial ,Article ,Loss of heterozygosity ,Transcriptome ,Fusion gene ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Thyroid Neoplasms ,Telomerase ,Genetics ,Chromosome Aberrations ,TOR Serine-Threonine Kinases ,Cell Biology ,medicine.disease ,Uniparental disomy ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Mutation ,Hurthle cell carcinoma ,Signal transduction ,Signal Transduction - Abstract
The molecular foundations of Hürthle cell carcinoma (HCC) are poorly understood. Here, we describe a comprehensive genomic characterization of 56 primary HCC tumors that span the spectrum of tumor behavior. We elucidate the mutational profile and driver mutations and show that they exhibit a wide range of recurrent mutations. Notably, we report an extremely high number of disruptive mutations to both protein-coding and tRNA-encoding regions of the mitochondrial genome. We reveal unique chromosomal landscapes that involve whole-chromosomal duplications of chromosomes 5 and 7 and widespread loss of heterozygosity arising from haploidization and copy number–neutral uniparental disomy. We also identify fusion genes and disrupted signaling pathways that may drive disease pathogenesis.
- Published
- 2018
38. Analysis of renal cancer cell lines from two major resources enables genomics-guided cell line selection
- Author
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Michael Chevinsky, A. Ari Hakimi, Christopher Jakubowski, Yiyu Dong, Ying-Bei Chen, Satish K. Tickoo, Andrew G. Winer, Rileen Sinha, Chris Sander, Victor E. Reuter, Paul Russo, Jonathan A. Coleman, and James J. Hsieh
- Subjects
0301 basic medicine ,Urology ,Science ,030232 urology & nephrology ,General Physics and Astronomy ,Genomics ,Computational biology ,Chromophobe cell ,Biology ,Kidney ,Bioinformatics ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Renal cell carcinoma ,Cell Line, Tumor ,medicine ,Carcinoma ,Humans ,Carcinoma, Renal Cell ,Selection (genetic algorithm) ,Multidisciplinary ,business.industry ,Genome, Human ,General Chemistry ,medicine.disease ,Kidney Neoplasms ,Human genetics ,3. Good health ,Clear cell renal cell carcinoma ,030104 developmental biology ,medicine.anatomical_structure ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Cancer cell lines ,business ,Kidney cancer - Abstract
The utility of cancer cell lines is affected by the similarity to endogenous tumour cells. Here we compare genomic data from 65 kidney-derived cell lines from the Cancer Cell Line Encyclopedia and the COSMIC Cell Lines Project to three renal cancer subtypes from The Cancer Genome Atlas: clear cell renal cell carcinoma (ccRCC, also known as kidney renal clear cell carcinoma), papillary (pRCC, also known as kidney papillary) and chromophobe (chRCC, also known as kidney chromophobe) renal cell carcinoma. Clustering copy number alterations shows that most cell lines resemble ccRCC, a few (including some often used as models of ccRCC) resemble pRCC, and none resemble chRCC. Human ccRCC tumours clustering with cell lines display clinical and genomic features of more aggressive disease, suggesting that cell lines best represent aggressive tumours. We stratify mutations and copy number alterations for important kidney cancer genes by the consistency between databases, and classify cell lines into established gene expression-based indolent and aggressive subtypes. Our results could aid investigators in analysing appropriate renal cancer cell lines., Cell lines are central to cancer research, but knowing which cell lines are the best representative of actual tumours is a major challenge. Here the authors provide a resource assessment of 65 renal cell lines to assist researchers in selecting suitable lines for studying specific renal carcinoma subtypes.
- Published
- 2017
39. MP88-17 PATIENT DERIVED XENOGRAFTS OF UPPER TRACT UROTHELIAL CARCINOMA: A POTENTIAL TOOL FOR PERSONALIZED MEDICINE
- Author
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Kwanghee Kim, Yiyu Dong, James J. Hsieh, Ricardo Alvim, Hikmat Al-Ahmadie, Aditya Bagrodia, Joanthan Rosenberg, A. Ari Hakimi, Alexander Somma, Katie S. Murray, Benjamin R. Gordon, Jonathan A. Coleman, Sylvia Jebiwott, Stephen LaRosa, David B. Solit, and François Audenet
- Subjects
Oncology ,medicine.medical_specialty ,Upper tract ,business.industry ,Urology ,Internal medicine ,medicine ,Personalized medicine ,business ,Urothelial carcinoma - Published
- 2017
40. MP71-03 DEVELOPMENT OF A CLEAR CELL RENAL CELL CARCINOMA XENOGRAFT MODEL: A CASE FOR THE USE OF BIOPSY TISSUE OVER SURGICAL TISSUE
- Author
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Brandon J. Manley, Jonathan A. Coleman, Paul Russo, James J. Hsieh, Yiyu Dong, A. Ari Hakimi, and Maria F. Becerra
- Subjects
Clear cell renal cell carcinoma ,Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Urology ,Biopsy ,Medicine ,business ,medicine.disease - Published
- 2016
41. Bio-inspired Computation Approach for Tumor Growth with Spatial Randomness Analysis of Kidney Cancer Xenograft Pathology Slides
- Author
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Yiyu Dong, James J. Hsieh, Aydin Saribudak, and M. Umit Uyar
- Subjects
education.field_of_study ,Mathematical model ,business.industry ,Computer science ,Computation ,Population ,Kernel density estimation ,Word error rate ,Pattern recognition ,k-nearest neighbors algorithm ,Differential evolution ,Artificial intelligence ,business ,education ,Randomness - Abstract
In this paper, we analyze digitized images of Hematoxylin-Eosin (H&E) slides equipped with tumorous tissues from patient derived xenograft models to build our bio-inspired computation method, namely Personalized Relevance Parameterization of Spatial Randomness (PReP-SR). Applying spatial pattern analysis techniques of quadrat counts, kernel estimation and nearest neighbor functions to the images of the H&E samples, slide-specific features are extracted to examine the hypothesis that existence of dependency of nuclei positions possesses information of individual tumor characteristics. These features are then used as inputs to PReP-SR to compute tumor growth parameters for exponential-linear model. Differential evolution algorithms are developed for tumor growth parameter computations, where a candidate vector in a population consists of size selection indices for spatial evaluation and weight coefficients for spatial features and their correlations. Using leave-one-out-cross-validation method, we showed that, for a set of H&E slides from kidney cancer patient derived xenograft models, PReP-SR generates personalized model parameters with an average error rate of 13.58%. The promising results indicate that bio-inspired computation techniques may be useful to construct mathematical models with patient specific growth parameters in clinical systems.
- Published
- 2016
42. A Pharmacologic Inhibitor of the Protease Taspase1 Effectively Inhibits Breast and Brain Tumor Growth
- Author
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David Piwnica-Worms, Yiyu Dong, Shugaku Takeda, Stanley J. Korsmeyer, Richard Gussio, David Y. Chen, Han Liu, Kyoung J. Oh, Robert H. Shoemaker, Adam C. Searleman, James J. Hsieh, Ho-Chou Tu, Ann R. Hermone, Brian A. Van Tine, Todd D. Westergard, Emily H. Cheng, and Yishan Lee
- Subjects
Male ,Cancer Research ,Cell Survival ,medicine.medical_treatment ,Molecular Sequence Data ,Cell ,Breast Neoplasms ,Biology ,Article ,Arsenicals ,Small Molecule Libraries ,Mice ,Therapeutic index ,Breast cancer ,Non-competitive inhibition ,Cell Line, Tumor ,Endopeptidases ,medicine ,Animals ,Humans ,Protease Inhibitors ,Amino Acid Sequence ,Amino Acids ,Cells, Cultured ,Mice, Knockout ,Binding Sites ,Protease ,Sequence Homology, Amino Acid ,Brain Neoplasms ,Mammary Neoplasms, Experimental ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,Molecular biology ,Small molecule ,Mice, Inbred C57BL ,Kinetics ,HEK293 Cells ,medicine.anatomical_structure ,Oncology ,Apoptosis ,Cancer research - Abstract
The threonine endopeptidase Taspase1 has a critical role in cancer cell proliferation and apoptosis. In this study, we developed and evaluated small molecule inhibitors of Taspase1 as a new candidate class of therapeutic modalities. Genetic deletion of Taspase1 in the mouse produced no overt deficiencies, suggesting the possibility of a wide therapeutic index for use of Taspase1 inhibitors in cancers. We defined the peptidyl motifs recognized by Taspase1 and conducted a cell-based dual-fluorescent proteolytic screen of the National Cancer Institute diversity library to identify Taspase1 inhibitors (TASPIN). On the basis of secondary and tertiary screens the 4-[(4-arsonophenyl)methyl]phenyl] arsonic acid NSC48300 was determined to be the most specific active compound. Structure–activity relationship studies indicated a crucial role for the arsenic acid moiety in mediating Taspase1 inhibition. Additional fluorescence resonance energy transfer–based kinetic analysis characterized NSC48300 as a reversible, noncompetitive inhibitor of Taspase1 (Ki = 4.22 μmol/L). In the MMTV-neu mouse model of breast cancer and the U251 xenograft model of brain cancer, NSC48300 produced effective tumor growth inhibition. Our results offer an initial preclinical proof-of-concept to develop TASPINs for cancer therapy. Cancer Res; 72(3); 736–46. ©2011 AACR.
- Published
- 2012
43. Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin
- Author
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Steven K. Albanese, Song Han, Vanessa Rodrik-Outmezguine, James J. Hsieh, David J. Chen, Zhan Yao, Daniel L. Parton, Jianing Xu, Yiyu Dong, Toshinao Oyama, John D. Chodera, Chung-Han Lee, Emily H. Cheng, Neal Rosen, and Can G. Pham
- Subjects
0301 basic medicine ,Male ,Mutation, Missense ,mTORC1 ,Mice, SCID ,Biology ,Molecular Dynamics Simulation ,DEPTOR ,medicine.disease_cause ,03 medical and health sciences ,Mice ,Protein Domains ,medicine ,Animals ,Humans ,Kinase activity ,RNA, Small Interfering ,Carcinoma, Renal Cell ,PI3K/AKT/mTOR pathway ,Sirolimus ,Mutation ,Antibiotics, Antineoplastic ,Kinase ,Genome, Human ,TOR Serine-Threonine Kinases ,RPTOR ,General Medicine ,Kidney Neoplasms ,3. Good health ,Kinetics ,030104 developmental biology ,Von Hippel-Lindau Tumor Suppressor Protein ,Cancer research ,Female ,medicine.drug ,DNA Damage ,Plasmids ,Research Article - Abstract
Genomic studies have linked mTORC1 pathway-activating mutations with exceptional response to treatment with allosteric inhibitors of mTORC1 called rapalogs. Rapalogs are approved for selected cancer types, including kidney and breast cancers. Here, we used sequencing data from 22 human kidney cancer cases to identify the activating mechanisms conferred by mTOR mutations observed in human cancers and advance precision therapeutics. mTOR mutations that clustered in focal adhesion kinase targeting domain (FAT) and kinase domains enhanced mTORC1 kinase activity, decreased nutrient reliance, and increased cell size. We identified 3 distinct mechanisms of hyperactivation, including reduced binding to DEP domain-containing MTOR-interacting protein (DEPTOR), resistance to regulatory associated protein of mTOR-mediated (RAPTOR-mediated) suppression, and altered kinase kinetics. Of the 28 mTOR double mutants, activating mutations could be divided into 6 complementation groups, resulting in synergistic Rag- and Ras homolog enriched in brain-independent (RHEB-independent) mTORC1 activation. mTOR mutants were resistant to DNA damage-inducible transcript 1-mediated (REDD1-mediated) inhibition, confirming that activating mutations can bypass the negative feedback pathway formed between HIF1 and mTORC1 in the absence of von Hippel-Lindau (VHL) tumor suppressor expression. Moreover, VHL-deficient cells that expressed activating mTOR mutants grew tumors that were sensitive to rapamycin treatment. These data may explain the high incidence of mTOR mutations observed in clear cell kidney cancer, where VHL loss and HIF activation is pathognomonic. Our study provides mechanistic and therapeutic insights concerning mTOR mutations in human diseases.
- Published
- 2015
44. Abstract 4619: Integrated genomic analysis of Hurthle cell carcinoma reveals TMEM233/PRKAB1 fusion as a novel oncogenic driver
- Author
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Ian Ganly, James A. Fagin, Gouri Nanjangud, Eric J. Sherman, Vladimir Makarov, Yiyu Dong, R. A. Ghossein, Ed Reznik, Luc G. T. Morris, Venkatraman Seshan, Shyamprasad Vasudeva Deraje, Fengshen Kuo, Timothy A. Chan, and Nadeem Riaz
- Subjects
Cancer Research ,Cancer ,Biology ,medicine.disease ,medicine.disease_cause ,Metastasis ,Thyroid carcinoma ,Loss of heterozygosity ,Fusion gene ,Oncology ,Cancer research ,medicine ,Carcinogenesis ,Thyroid cancer ,Exome sequencing - Abstract
Background: Hurthle cell carcinoma (HCC) is an enigmatic malignancy of the thyroid that can behave in an aggressive fashion, sometimes lethal, yet its molecular foundations are poorly understood. Some HCC have a good prognosis (minimally invasive, HMIN) whereas others can be extremely aggressive (widely invasive, HWIDE), leading to metastasis and death. HCCs were not included in the TCGA thyroid cancer study, which focused solely on papillary thyroid carcinomas. To understand the development of HCC and unveil its molecular mechanism, we performed a comprehensive genomic characterization of 56 primary HCCs that span the spectrum of tumor behavior and investigated the role of TMEM233/PRKAB1 fusion as a critical driver of oncogenesis in HCC. Methods: Tumor and matched normal specimens were obtained from 56 patients with primary HCC. Tumors were classified into minimally invasive ( n=24) or widely invasive subtype (n=32). Whole exome sequencing was used to identify somatic mutations. Copy number changes were identified using FACETS and validated by FISH. RNASeq was used to identify novel fusions genes and to identify differentially expressed genes. Genomic alterations associated with histological phenotype were identified. Genomic changes associated with recurrence and survival were identified by the Kaplan Meier method. Immortalized thyroid epithelial cell line, NTHY-ori 3.1 was used to express control and fusion gene for in vitro and in vivo experiments. Results: We elucidate the mutational profile and driver mutations in HCC and reveal that they exhibit a diverse spectrum of recurrent mutations, most of which have not been previously associated with this cancer (EIF1AX, MADCAM1). Notably, HCC harbor an extremely high prevalence of disruptive mutations to both protein-coding and tRNA encoding regions of the mitochondrial genome. We reveal unique chromosomal landscapes that involve whole chromosomal duplications of chromosomes 5 and 7 and wide spread major loss of heterozygosity arising from haploidization and copy number neutral uniparental disomy. These chromosomal processes underlie genetic instability and are highly prevalent in aggressive forms of HCC. We also identify novel fusion genes such as TMEM233/PRKAB1 which expression resulted in a transformation, organoids formation and invasion phenotype in vitro and tumorigenesis in vivo. These data suggested that TMEM233/PRKAB1 fusion plays as a critical driver and may serve as a therapeutic target for HCCs. Conclusions: We performed integrated genomic analysis of hurthle cell carcinoma revealing novel oncogenic drivers, recurrent mitochondrial mutations and unique chromosomal landscapes, which will help guide development of new treatments for one of the most deadly types of thyroid cancer. Citation Format: Yiyu Dong, Ian Ganly, Vladimir Makarov, Fengshen Kuo, Shyamprasad Deraje, Ed Reznik, Venkatraman Seshan, Gouri Nanjangud, Luc Morris, Nadeem Riaz, Eric Sherman, Ronald Ghossein, James Fagin, Timothy Chan. Integrated genomic analysis of Hurthle cell carcinoma reveals TMEM233/PRKAB1 fusion as a novel oncogenic driver [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 4619.
- Published
- 2018
45. Synthetic Lethality through Combined Notch–Epidermal Growth Factor Receptor Pathway Inhibition in Basal-Like Breast Cancer
- Author
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Loren S. Michel, Yiyu Dong, Jianbo Wang, Aimin Li, and Jason D. Weber
- Subjects
Cancer Research ,Cell signaling ,medicine.medical_specialty ,Cell Survival ,Notch signaling pathway ,Antineoplastic Agents ,Breast Neoplasms ,Cell Growth Processes ,Synthetic lethality ,Biology ,Mice ,Gefitinib ,Growth factor receptor ,Cell Line, Tumor ,Internal medicine ,medicine ,Animals ,Humans ,Epidermal growth factor receptor ,Protein Kinase Inhibitors ,Protein kinase B ,Benzodiazepinones ,Receptors, Notch ,Dipeptides ,Xenograft Model Antitumor Assays ,Enzyme Activation ,ErbB Receptors ,Endocrinology ,Oncology ,Quinazolines ,Cancer research ,biology.protein ,Cyclin-dependent kinase 8 ,Female ,Amyloid Precursor Protein Secretases ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,medicine.drug - Abstract
Basal-like breast cancers (BLBC) are highly aggressive, yet selective therapies targeting the specific oncoproteins driving these tumors have not been developed. These cancers frequently express epidermal growth factor receptor (EGFR), with resistance to its inhibition being well documented, albeit poorly understood. Notch pathway activation is also common in this breast cancer subtype and can be suppressed by γ-secretase inhibitors, which effectively block receptor cleavage and activation. Herein, we show that although inhibition of either EGFR or Notch signaling alone is insufficient to suppress basal-like breast tumor cell survival and proliferation, simultaneous inhibition uncovers a synthetic lethal relationship between these two oncogenic pathways. This lethality is due in part to significant decreases in AKT activation caused by combined EGFR and Notch inhibition. Expression of the activated form of Notch1 restores AKT activity and enables cells to overcome cell death after dual-pathway blockade. Combined pathway inhibition is also dramatically more effective at suppressing tumor growth in mice than blocking EGFR or Notch signaling alone. Thus, we show that Notch pathway activation contributes to resistance to EGFR inhibition, and provide a novel treatment strategy for BLBCs. Cancer Res; 70(13); 5465–74. ©2010 AACR.
- Published
- 2010
46. Mathematical models of tumor growth using Voronoi tessellations in pathology slides of kidney cancer
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M. Umit Uyar, Stephen Gundry, Yiyu Dong, James J. Hsieh, and Aydin Saribudak
- Subjects
Cell Nucleus ,Microscopy ,Pathology ,medicine.medical_specialty ,Mathematical model ,Models, Theoretical ,Biology ,medicine.disease ,Tumor tissue ,Kidney Neoplasms ,Mice ,Preclinical phase ,Feature (computer vision) ,medicine ,Animals ,Humans ,Tumor growth ,Voronoi diagram ,Kidney cancer - Abstract
The impact of patient-specific spatial distribution features of cell nuclei on tumor growth characteristics was analyzed. Tumor tissues from kidney cancer patients were allowed to grow in mice to apply H&E staining and to measure tumor volume during preclinical phase of our study. Imaging the H&E stained slides under a digital light microscope, the morphological characteristics of nuclei positions were determined. Using artificial intelligence based techniques, Voronoi features were derived from diagrams, where cell nuclei were considered as distinct nodes. By identifying the effect of each Voronoi feature, tumor growth was expressed mathematically. Consistency between the computed growth curves and preclinical measurements indicates that the information obtained from the H&E slides can be used as biomarkers to build personalized mathematical models for tumor growth.
- Published
- 2015
47. Obtaining and analysis of flanking sequences from T-DNA transformants of Arabidopsis
- Author
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Genji Qin, Weiran Niu, Li Zhang, Jigang Li, Yanfei Ren, Hongya Gu, Yunping Shen, Nan Chen, Haodong Chen, Li-Jia Qu, Dingming Kang, Xing Wang Deng, Zhangliang Chen, Xiaohui Deng, Yiyu Dong, Peicheng Liu, Song Li, Yao Zhang, and Cong Chen
- Subjects
Genetics ,biology ,Agrobacterium ,Genomics ,Plant Science ,General Medicine ,biology.organism_classification ,Transformation (genetics) ,chemistry.chemical_compound ,chemistry ,Arabidopsis ,Arabidopsis thaliana ,Agronomy and Crop Science ,Gene ,Functional genomics ,DNA - Abstract
Large collections of insertional Arabidopsis lines are valuable for research on functional genomics. Using the activation tagging vector pSKI015, more than 45 000 T-DNA insertion lines were generated by Agrobacterium -mediated floral-dip transformation protocol. 2304 insertion lines were analyzed and 1502 items of plant sequences flanking the T-DNA insertion sites were obtained by a modified thermal asymmetric interlaced PCR (TAIL-PCR) protocol. These sequences were searched against Genebank database using blast and 1194 insertion sites were determined according to the sequences matching to the Arabidopsis genome sequence. The insertion sites were distributed on all the five Arabidopsis chromosomes and the interfered genes were classified into 14 function categories. Analysis on 1194 items of 100-bp sequences surrounding T-DNA insertion sites showed that 27 and 31% GC contents were likely to favor the T-DNA integration. Sixty-eight items of these 100-bp sequences having more than two insertions were chosen to look for motifs in favor of T-DNA integration. The results showed that “ATNTT” (N represents A/T/C/G) and the polyT and polyA motifs probably play a role in the T-DNA integration event.
- Published
- 2003
48. Patient derived xenografts of upper tract urothelial carcinoma: A potential tool for personalized medicine
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A. Ari Hakimi, François Audenet, Stephen LaRosa, Hikmat Al-Ahmadie, Alex Somma, Aditya Bagrodia, David B. Solit, Benjamin R. Gordon, Kwanghee Kim, James J. Hsieh, Jonathan A. Coleman, Yiyu Dong, Jonathan E. Rosenberg, Ricardo Alvim, Sylvia Jebiwott, and Katie S. Murray
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,business.industry ,Clinical course ,Upper tract ,Internal medicine ,Medicine ,In patient ,Personalized medicine ,business ,Urothelial carcinoma - Abstract
344 Background: Historically, upper tract urothelial carcinomas (UTUC) are treated similarly to urothelial carcinoma of the bladder (UCB). However, compared to UCB, UTUC demonstrates a more aggressive clinical course which may be explained by significant differences in mutational frequencies between UTUC and UCB that were reported using a customized exon capture sequencing assay (the MSK-IMPACT assay). A major limitation in the advancement of the UTUC field is the lack of appropriate models specific to the disease. The objective of this study was to develop and evaluate preclinical models that would recapitulate treatment responses observed in patients. Methods: 35 surgical specimens from nephroureterectomy of patients with UTUC were implanted into immunocompromised NOD-SCID IL2Rg−/− (NSG) mice. The histological and the genomic characterization of patient tumors and PDXs were examined by a board certified pathologist and MSK-IMPACT assay, respectively. Cell lines were also established to assess histologic and genetic fidelity. Chemosensitivity of PDX models was assessed using a 4 week cycle of gemcitabine/cisplatin (or carboplatin) administration and analysis of tumor growth was performed using a Two-way ANOVA test. Results: 12 patient-derived xenograft (PDX) models were established with a success rate of 34% (12/35) and a 14% (3/21) success in developing cell lines. Both models were highly reflective of their original tumors in terms of histology and genomic characteristics in mutation status and copy number alterations. For a representative PDX, chemosensitivity experiments identified gemcitabine/carboplatin as a potentially effective combination, which was also used in the clinical scenario with a therapeutic response. Chemosensitivity of additional PDXs is continuing to be investigated to potentially guide post-operative decision making for treatment of the patient’s clinically. Conclusions: We developed a cohort of stable PDX models and cell lines for UTUC that maintains the genetic characteristics of the patient’s initial tumor. The continued development of these models may facilitate personalized medicine strategies in the treatment of UTUC.
- Published
- 2017
49. Taspase1 cleaves MLL1 to activate cyclin E for HER2/neu breast tumorigenesis
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Yiyu Dong, Patricia Wang, Emily H. Cheng, James J. Hsieh, Toshinao Oyama, and Brian A. Van Tine
- Subjects
Genetically modified mouse ,MLL ,Cyclin E ,Genotype ,Receptor, ErbB-2 ,Mammary gland ,Breast Neoplasms ,Mice, Transgenic ,Biology ,medicine.disease_cause ,HER2/neu ,Cell Line ,Mice ,Breast cancer ,Mammary Glands, Animal ,breast cancer ,Pregnancy ,HER2 ,Endopeptidases ,medicine ,Animals ,Humans ,Lactation ,skin and connective tissue diseases ,Molecular Biology ,neoplasms ,Alleles ,Cyclin ,Cell Proliferation ,Cell growth ,Cell Biology ,Histone-Lysine N-Methyltransferase ,medicine.disease ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Taspase1 ,Cancer research ,biology.protein ,Mutagenesis, Site-Directed ,Female ,RNA Interference ,Original Article ,Carcinogenesis ,Cyclin-Dependent Kinase Inhibitor p27 ,Myeloid-Lymphoid Leukemia Protein - Abstract
Taspase1, a highly conserved threonine protease, cleaves nuclear transcriptional regulators mixed-lineage leukemia (MLL, MLL1), MLL2, TFIIA, and ALF to orchestrate a wide variety of biological processes. In vitro studies thus far demonstrated that Taspase1 plays important roles in the proliferation of various cancer cell lines, including HER2-positive breast cancer cells. To investigate the role of Taspase1 in breast tumorigenesis in vivo, we deleted Taspase1 from mouse mammary glands by generating MMTV-neu;MMTV-cre;Tasp1(F/-) mice. We demonstrate that initiation of MMTV-neu- but not MMTV-wnt-driven breast cancer is blocked in the absence of Taspase1. Importantly, Taspase1 loss alone neither impacts normal development nor pregnancy physiology of the mammary gland. In mammary glands Taspase1 deficiency abrogates MMTV-neu-induced cyclins E and A expression, thereby preventing tumorigenesis. The mechanisms were explored in HER2-positive breast cancer cell line BT474 and HER2-transformed MCF10A cells and validated using knockdown-resistant Taspase1. As Taspase1 was shown to cleave MLL which forms complexes with E2F transcription factors to regulate Cyclins E, A, and B expression in mouse embryonic fibroblasts (MEFs), we investigated whether the cleavage of MLL by Taspase1 constitutes an essential in vivo axis for HER2/neu-induced mammary tumorigenesis. To this end, we generated MMTV-neu;MLL(nc/nc) transgenic mice that carry homozygous non-cleavable MLL alleles. Remarkably, these mice are also protected from HER2/neu-driven breast tumorigenesis. Hence, MLL is the primary Taspase1 substrate whose cleavage is required for MMTV-neu-induced tumor formation. As Taspase1 plays critical roles in breast cancer pathology, it may serve as a therapeutic target for HER2-positive human breast cancer.
- Published
- 2014
50. PUMA and BIM are required for oncogene inactivation-induced apoptosis
- Author
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Han Liu, James J. Hsieh, Yiyu Dong, Gregory R. Bean, Emily H. Cheng, Yogesh Tengarai Ganesan, Yafen Huang, Gerard P. Zambetti, Shugaku Takeda, Po M. Chan, and Lewis A. Chodosh
- Subjects
MAPK/ERK pathway ,Receptor, ErbB-2 ,Apoptosis ,Biochemistry ,Piperazines ,Nitrophenols ,Mice ,Puma ,hemic and lymphatic diseases ,Epidermal growth factor receptor ,RNA, Small Interfering ,Sulfonamides ,biology ,Bcl-2-Like Protein 11 ,Kinase ,Reverse Transcriptase Polymerase Chain Reaction ,Protein-Tyrosine Kinases ,Flow Cytometry ,Immunohistochemistry ,ErbB Receptors ,Female ,RNA Interference ,Signal transduction ,biological phenomena, cell phenomena, and immunity ,Tyrosine kinase ,Plasmids ,Signal Transduction ,Chromatin Immunoprecipitation ,MAP Kinase Signaling System ,Immunoblotting ,Breast Neoplasms ,Article ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Animals ,Humans ,Gene Silencing ,Protein kinase A ,Molecular Biology ,PI3K/AKT/mTOR pathway ,Biphenyl Compounds ,Membrane Proteins ,Lapatinib ,Cell Biology ,Oncogenes ,biology.organism_classification ,Cancer research ,biology.protein ,Quinazolines ,Apoptosis Regulatory Proteins - Abstract
The clinical efficacy of tyrosine kinase inhibitors supports the dependence of distinct subsets of cancers on specific driver mutations for survival, a phenomenon called "oncogene addiction." We demonstrate that PUMA and BIM are the key apoptotic effectors of tyrosine kinase inhibitors in breast cancers with amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) and lung cancers with epidermal growth factor receptor (EGFR) mutants. The BH3 domain containing proteins BIM and PUMA can directly activate the proapoptotic proteins BAX and BAK to permeabilize mitochondria, leading to caspase activation and apoptosis. We delineated the signal transduction pathways leading to the induction of BIM and PUMA by tyrosine kinase inhibitors. Inhibition of the mitogen-activated or extracellular signal-regulated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway caused increased abundance of BIM, whereas antagonizing the phosphoinositide 3-kinase (PI3K)-AKT pathway triggered nuclear translocation of the FOXO transcription factors, which directly activated the PUMA promoter. In a mouse breast tumor model, the abundance of PUMA and BIM was increased after inactivation of HER2. Moreover, deficiency of Bim or Puma impaired caspase activation and reduced tumor regression caused by inactivation of HER2. Similarly, deficiency of Puma impeded the regression of EGFR(L858R)-driven mouse lung tumors upon inactivation of the EGFR-activating mutant. Overall, our study identified PUMA and BIM as the sentinels that interconnect kinase signaling networks and the mitochondrion-dependent apoptotic program, which offers therapeutic insights for designing novel cell death mechanism-based anticancer strategies.
- Published
- 2013
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