128 results on '"Samuels Y"'
Search Results
2. Investigation of the Melanoma Genetic Landscape Identifies the Glutamate Pathway as a Major Player in the Disease: FC-034
- Author
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Samuels, Y.
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- 2013
3. The impact of the cancer genome project and high-throughput analyses on personalised oncology: today and tomorrow
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Samuels, Y., Prickett, T.D., Wei, X., Lin, J.C., Teer, J.K., and Rosenberg, S.A.
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- 2012
4. Prevalence of anti-hepatitis A antibodies, hepatitis B viral markers, and anti-hepatitis C antibodies among immigrants from the former USSR who arrived in israel during 1990–1991
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Almog, R., Low, M., Cohen, D., Robin, G., Ashkenazi, S., Bercovier, H., Gdalevich, M., Samuels, Y., Ashkenazi, I., Shermer, J., Aldad, A., and Green, M. S.
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- 1999
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5. 24 Combined analysis of antigen presentation and T cell recognition reveals restricted immune responses in melanoma
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Kalaora, S., primary, Wolf, Y., additional, Reuben, A., additional, Rosenberg, S.A., additional, Lotem, M., additional, Sahin, U., additional, Wargo, J., additional, Friedman, N., additional, Admon, A., additional, and Samuels, Y., additional
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- 2018
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6. The equilibrium phase properties of the propane-methanol andn-Butane-methanol binary systems
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Ah-Dong Lev, Donald B. Robinson, C.-J. Chen, and Samuels Y.-K. Chung
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chemistry.chemical_compound ,chemistry ,True vapor pressure ,Propane ,Vapor pressure ,General Chemical Engineering ,Azeotrope ,Vapour pressure of water ,Thermodynamics ,Vapor–liquid equilibrium ,Butane ,Binary system - Abstract
Vapor and liquid equilibrium phase compositions were determined at 310.7, 352.2, 393.0 and 474.3 K for the propane-methanol system and at 469.9 K for the n-butane–methanol system. Measurements were made at pressures from the vapor pressure of the less volatile component to the maximum pressure where two phases coexisted either as an azeo-trope or at the critical condition, depending on the system. Azeotropic behavior was observed at 310.7 and 352.2 K for the propane-methanol system. Equilibrium ratios were calculated at each temperature from the phase composition data. The temperature dependence of the azeotrope pressure and of the corresponding azeotrope composition was expressed analytically.
- Published
- 1992
7. Colorectal cancer: mutations in a signalling pathway
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Parsons, Dw, Wang, Tl, Samuels, Y., Bardelli, Alberto, Cummins, Jm, Delong, L., Silliman, N., Ptak, J., Szabo, S., Willson, Jk, Markowitz, S., Kinzler, Kw, Vogelstein, B., Lengauer, C., and Velculescu, Ve
- Subjects
Phosphatidylinositol 3-Kinases ,DNA Mutational Analysis ,Mutation ,Humans ,Exons ,Protein Serine-Threonine Kinases ,Colorectal Neoplasms ,Polymerase Chain Reaction ,Protein Structure, Tertiary ,Signal Transduction - Abstract
Protein kinases are enzymes that are important for controlling cellular growth and invasion, and their malfunction is implicated in the development of some tumours. We analysed human colorectal cancers for genetic mutations in 340 serine/threonine kinases and found mutations in eight genes, including in three members of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway. The discovery of this mutational activation of a key cell-signalling pathway may provide new targets for therapeutic intervention.
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- 2005
8. Towards Deciphering the Genetic Landscape in Melanoma
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Samuels, Y., primary, Prickett, T.D., additional, Wei, X., additional, Lin, J.C., additional, Teer, J.K., additional, and Rosenberg, S.A., additional
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- 2012
- Full Text
- View/download PDF
9. The equilibrium phase properties of the propane‐methanol and n‐Butane‐methanol binary systems
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Lev, Ah‐Dong, primary, Robinson, Donald B., additional, Chung, Samuels Y.‐K., additional, and Chen, C.‐J., additional
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- 1992
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10. Oncogenic PI3K and its role in cancer.
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Samuels Y, Ericson K, Samuels, Yardena, and Ericson, Kajsa
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- 2006
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11. Erratum: The PIK3CA gene is mutated with high frequency in human breast cancers (Cancer Biology and Therapy (2004) 3 (772-775))
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Lin, L., Bachman, K. E., Ellis, M., Ben, H. P., Argani, P., Samuels, Y., Silliman, N., Ptak, J., Szabo, S., Hiroyuki Konishi, Karakas, B., Blair, B. G., Lin, C., Peters, B. A., Velculescu, V. E., and Park, B. H.
12. A highly recurrent RPS27 5'UTR mutation in melanoma
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Dutton-Regester, K., Gartner, J. J., Emmanuel, R., Qutob, N., Davies, M. A., Gershenwald, J. E., Robinson, W., Robinson, S., Rosenberg, S. A., Richard Scolyer, Mann, G. J., Thompson, J. F., Hayward, N. K., and Samuels, Y.
13. The cancer genome
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Samuels, Y., Bardelli, A., Gartner, J. J., and Carlos López-Otín
14. Comparative exome sequencing of metastatic lesions provides insights into the mutational progression of melanoma
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Gartner Jared J, Davis Sean, Wei Xiaomu, Lin Jimmy C, Trivedi Niraj S, Teer Jamie K, Meltzer Paul S, Rosenberg Steven A, and Samuels Yardena
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Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Metastasis is characterized by spreading of neoplastic cells to an organ other than where they originated and is the predominant cause of death among cancer patients. This holds true for melanoma, whose incidence is increasing more rapidly than any other cancer and once disseminated has few therapeutic options. Here we performed whole exome sequencing of two sets of matched normal and metastatic tumor DNAs. Results Using stringent criteria, we evaluated the similarities and differences between the lesions. We find that in both cases, 96% of the single nucleotide variants are shared between the two metastases indicating that clonal populations gave rise to the distant metastases. Analysis of copy number variation patterns of both metastatic sets revealed a trend similar to that seen with our single nucleotide variants. Analysis of pathway enrichment on tumor sets shows commonly mutated pathways enriched between individual sets of metastases and all metastases combined. Conclusions These data provide a proof-of-concept suggesting that individual metastases may have sufficient similarity for successful targeting of driver mutations.
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- 2012
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15. iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72-polymorphic p53
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Tim Crook, Giannino Del Sal, Alexandra Sullivan, Daniele Bergamaschi, Andrea Bisso, Xin Lu, Nelofer Syed, Marketa Zvelebil, Milena Gasco, Paul D. Smith, Hilde Breyssens, Yardena Samuels, Bergamaschi, D, Samuels, Y, Sullivan, A, Zvelebil, M, Breyssens, H, Bisso, A, DEL SAL, Giannino, Syed, N, Smith, P, Gasco, M, Crook, T, and Lu, X.
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Proline ,Tumor suppressor gene ,Arginine ,Molecular Sequence Data ,Repressor ,Apoptosis ,Breast Neoplasms ,Biology ,Conserved sequence ,Genetics ,Humans ,Amino Acid Sequence ,Tyrosine ,Binding site ,Codon ,Peptide sequence ,Cells, Cultured ,Conserved Sequence ,Regulation of gene expression ,Binding Sites ,Polymorphism, Genetic ,Carcinoma ,Homozygote ,Intracellular Signaling Peptides and Proteins ,Repressor Proteins ,Gene Expression Regulation ,Female ,Tumor Suppressor Protein p53 - Abstract
iASPP is one of the most evolutionarily conserved inhibitors of p53, whereas ASPP1 and ASPP2 are activators of p53. We show here that, in addition to the DNA-binding domain, the ASPP family members also bind to the proline-rich region of p53, which contains the most common p53 polymorphism at codon 72. Furthermore, the ASPP family members, particularly iASPP, bind to and regulate the activity of p53Pro72 more efficiently than that of p53Arg72. Hence, escape from negative regulation by iASPP is a newly identified mechanism by which p53Arg72 activates apoptosis more efficiently than p53Pro72.
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- 2006
16. Author Correction: Breaking the performance ceiling for neoantigen immunogenicity prediction.
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O'Brien H, Salm M, Morton LT, Szukszto M, O'Farrell F, Boulton C, Becker PD, Samuels Y, Swanton C, Mansour MR, Reker Hadrup S, and Quezada SA
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- 2024
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17. Breaking the performance ceiling for neoantigen immunogenicity prediction.
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O'Brien H, Salm M, Morton LT, Szukszto M, O'Farrell F, Boulton C, Becker PD, Samuels Y, Swanton C, Mansour MR, Reker Hadrup S, and Quezada SA
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- Humans, Antigens, Neoplasm genetics
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- 2023
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18. Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion.
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Cohen Shvefel S, Pai JA, Cao Y, Pal LR, Levy R, Yao W, Cheng K, Zemanek M, Bartok O, Weller C, Yin Y, Du PP, Yakubovich E, Orr I, Ben-Dor S, Oren R, Fellus-Alyagor L, Golani O, Goliand I, Ranmar D, Savchenko I, Ketrarou N, Schäffer AA, Ruppin E, Satpathy AT, and Samuels Y
- Abstract
Decreased intra-tumor heterogeneity (ITH) correlates with increased patient survival and immunotherapy response. However, even highly homogenous tumors may display variability in their aggressiveness, and how immunologic-factors impinge on their aggressiveness remains understudied. Here we studied the mechanisms responsible for the immune-escape of murine tumors with low ITH. We compared the temporal growth of homogeneous, genetically-similar single-cell clones that are rejected vs. those that are not-rejected after transplantation in-vivo using single-cell RNA sequencing and immunophenotyping. Non-rejected clones showed high infiltration of tumor-associated-macrophages (TAMs), lower T-cell infiltration, and increased T-cell exhaustion compared to rejected clones. Comparative analysis of rejection-associated gene expression programs, combined with in-vivo CRISPR knockout screens of candidate mediators, identified Mif (macrophage migration inhibitory factor) as a regulator of immune rejection. Mif knockout led to smaller tumors and reversed non-rejection-associated immune composition, particularly, leading to the reduction of immunosuppressive macrophage infiltration. Finally, we validated these results in melanoma patient data., Competing Interests: Conflict of interest: A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Astellas and Merck Research Laboratories. E.R. is a co-founder of MedAware Ltd and a co-founder (divested) and non-paid scientific consultant of Pangea Biomed. The other authors declare that they have no potential conflicts of interest.
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- 2023
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19. The landscape of T cell antigens for cancer immunotherapy.
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Peri A, Salomon N, Wolf Y, Kreiter S, Diken M, and Samuels Y
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- Humans, T-Lymphocytes, Antigens, Neoplasm, Immunotherapy, Neoplasms therapy
- Abstract
The remarkable capacity of immunotherapies to induce durable regression in some patients with metastatic cancer relies heavily on T cell recognition of tumor-presented antigens. As checkpoint-blockade therapy has limited efficacy, tumor antigens have the potential to be exploited for complementary treatments, many of which are already in clinical trials. The surge of interest in this topic has led to the expansion of the tumor antigen landscape with the emergence of new antigen categories. Nonetheless, how different antigens compare in their ability to elicit efficient and safe clinical responses remains largely unknown. Here, we review known cancer peptide antigens, their attributes and the relevant clinical data and discuss future directions., (© 2023. Springer Nature America, Inc.)
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- 2023
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20. The proteasome regulator PSME4 modulates proteasome activity and antigen diversity to abrogate antitumor immunity in NSCLC.
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Javitt A, Shmueli MD, Kramer MP, Kolodziejczyk AA, Cohen IJ, Radomir L, Sheban D, Kamer I, Litchfield K, Bab-Dinitz E, Zadok O, Neiens V, Ulman A, Wolf-Levy H, Eisenberg-Lerner A, Kacen A, Alon M, Rêgo AT, Stacher-Priehse E, Lindner M, Koch I, Bar J, Swanton C, Samuels Y, Levin Y, da Fonseca PCA, Elinav E, Friedman N, Meiners S, and Merbl Y
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- Humans, Antigen Presentation, Precision Medicine, Proteasome Endopeptidase Complex metabolism, Tumor Microenvironment, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms pathology
- Abstract
Immunotherapy revolutionized treatment options in cancer, yet the mechanisms underlying resistance in many patients remain poorly understood. Cellular proteasomes have been implicated in modulating antitumor immunity by regulating antigen processing, antigen presentation, inflammatory signaling and immune cell activation. However, whether and how proteasome complex heterogeneity may affect tumor progression and the response to immunotherapy has not been systematically examined. Here, we show that proteasome complex composition varies substantially across cancers and impacts tumor-immune interactions and the tumor microenvironment. Through profiling of the degradation landscape of patient-derived non-small-cell lung carcinoma samples, we find that the proteasome regulator PSME4 is upregulated in tumors, alters proteasome activity, attenuates presented antigenic diversity and associates with lack of response to immunotherapy. Collectively, our approach affords a paradigm by which proteasome composition heterogeneity and function should be examined across cancer types and targeted in the context of precision oncology., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2023
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21. Large-Scale Immunopeptidome Analysis Reveals Recurrent Posttranslational Splicing of Cancer- and Immune-Associated Genes.
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Levy R, Alter Regev T, Paes W, Gumpert N, Cohen Shvefel S, Bartok O, Dayan-Rubinov M, Alon M, Shmueli MD, Levin Y, Merbl Y, Ternette N, and Samuels Y
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- Animals, Mice, RNA Splicing, Peptides metabolism, Histocompatibility Antigens Class I genetics, Histocompatibility Antigens Class I metabolism, Neoplasms genetics
- Abstract
Posttranslational spliced peptides (PTSPs) are a unique class of peptides that have been found to be presented by HLA class-I molecules in cancer. Thus far, no consensus has been reached on the proportion of PTSPs in the immunopeptidome, with estimates ranging from 2% to as high as 45% and stirring significant debate. Furthermore, the role of the HLA class-II pathway in PTSP presentation has been studied only in diabetes. Here, we exploit our large-scale cancer peptidomics database and our newly devised pipeline for filtering spliced peptide predictions to identify recurring spliced peptides, both for HLA class-I and class-II complexes. Our results indicate that HLA class-I-spliced peptides account for a low percentage of the immunopeptidome (less than 3.1%) yet are larger in number relative to other types of identified aberrant peptides. Therefore, spliced peptides significantly contribute to the repertoire of presented peptides in cancer cells. In addition, we identified HLA class-II-bound spliced peptides, but to a lower extent (less than 0.5%). The identified spliced peptides include cancer- and immune-associated genes, such as the MITF oncogene, DAPK1 tumor suppressor, and HLA-E, which were validated using synthetic peptides. The potential immunogenicity of the DAPK1- and HLA-E-derived PTSPs was also confirmed. In addition, a reanalysis of our published mouse single-cell clone immunopeptidome dataset showed that most of the spliced peptides were found repeatedly in a large number of the single-cell clones. Establishing a novel search-scheme for the discovery and evaluation of recurring PTSPs among cancer patients may assist in identifying potential novel targets for immunotherapy., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of the article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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22. Post-translational modifications reshape the antigenic landscape of the MHC I immunopeptidome in tumors.
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Kacen A, Javitt A, Kramer MP, Morgenstern D, Tsaban T, Shmueli MD, Teo GC, da Veiga Leprevost F, Barnea E, Yu F, Admon A, Eisenbach L, Samuels Y, Schueler-Furman O, Levin Y, Nesvizhskii AI, and Merbl Y
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- Humans, Peptides genetics, Antigens, Histocompatibility Antigens Class I genetics, Histocompatibility Antigens Class I metabolism, Protein Processing, Post-Translational genetics, Neoplasms genetics
- Abstract
Post-translational modification (PTM) of antigens provides an additional source of specificities targeted by immune responses to tumors or pathogens, but identifying antigen PTMs and assessing their role in shaping the immunopeptidome is challenging. Here we describe the Protein Modification Integrated Search Engine (PROMISE), an antigen discovery pipeline that enables the analysis of 29 different PTM combinations from multiple clinical cohorts and cell lines. We expanded the antigen landscape, uncovering human leukocyte antigen class I binding motifs defined by specific PTMs with haplotype-specific binding preferences and revealing disease-specific modified targets, including thousands of new cancer-specific antigens that can be shared between patients and across cancer types. Furthermore, we uncovered a subset of modified peptides that are specific to cancer tissue and driven by post-translational changes that occurred in the tumor proteome. Our findings highlight principles of PTM-driven antigenicity, which may have broad implications for T cell-mediated therapies in cancer and beyond., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2023
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23. NRas activity is regulated by dynamic interactions with nanoscale signaling clusters at the plasma membrane.
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Yakovian O, Sajman J, Alon M, Arafeh R, Samuels Y, and Sherman E
- Abstract
NRas is a key mediator of the mitogenic pathway in normal cells and in cancer cells. Its dynamics and nanoscale organization at the plasma membrane (PM) facilitate its signaling. Here, we used two-color photoactivated localization microscopy to resolve the organization of individual NRas and associated signaling proteins in live melanoma cells, with resolution down to ∼20 nm. Upon EGF activation, a fraction of NRas and BRAF (dis)assembled synchronously at the PM in co-clusters. NRas and BRAF clusters associated with GPI-enriched domains, serving as possible nucleation sites for these clusters. NRas and BRAF association in mutual clusters was reduced by the NRas farnesylation inhibitor lonafarnib, yet enhanced by the BRAF inhibitor vemurafenib. Surprisingly, dispersed NRas molecules associated with the periphery of self-clusters of either Grb2 or NF1. Thus, NRas-mediated signaling, which is critical in health and disease, is regulated by dynamic interactions with functional clusters of BRAF or other related proteins at the PM., Competing Interests: The authors declare no potential conflicts of interest., (© 2022 The Authors.)
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- 2022
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24. Intratumor Heterogeneity and Antitumor Immunity Shape One Another Bidirectionally.
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Wolf Y and Samuels Y
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- Antigens, Neoplasm, Biomarkers, Tumor genetics, Humans, Mutation, Tumor Microenvironment genetics, Genetic Heterogeneity, Neoplasms genetics
- Abstract
Over the last decade, it has become clear that the genomic landscapes of tumors profoundly impact their immunogenicity and how tumor cells interact with immune cells. Whereas past discoveries mainly focused on the interplay between tumor immunogenicity and tumor mutational burden (TMB), under the assumption that a higher mutation load would give rise to a better patient response to immune checkpoint blockade therapies, we and others have underlined intratumor heterogeneity (ITH) as an important determinant of the magnitude of the antitumor response and the nature of the tumor microenvironment. In this review, we define TMB versus ITH and how the two factors are being inferred from data, examine key findings in the cancer immunogenomics literature deciphering the complex cross-talk between TMB, ITH, and antitumor immunity in human cancers and in vivo models, and discuss the mutual influence of ITH and immunity-how the antitumor response can give rise to tumors with higher ITH, and how higher ITH can put shackles on the antitumor response., (©2022 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2022
- Full Text
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25. Mechanisms of immune activation and regulation: lessons from melanoma.
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Kalaora S, Nagler A, Wargo JA, and Samuels Y
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- Humans, Immunotherapy, Tumor Escape genetics, Tumor Microenvironment, Melanoma genetics, Skin Neoplasms pathology
- Abstract
Melanoma, a skin cancer that develops from pigment cells, has been studied intensively, particularly in terms of the immune response to tumours, and has been used as a model for the development of immunotherapy. This is due, in part, to the high mutational burden observed in melanomas, which increases both their immunogenicity and the infiltration of immune cells into the tumours, compared with other types of cancers. The immune response to melanomas involves a complex set of components and interactions. As the tumour evolves, it accumulates an increasing number of genetic and epigenetic alterations, some of which contribute to the immunogenicity of the tumour cells and the infiltration of immune cells. However, tumour evolution also enables the development of resistance mechanisms, which, in turn, lead to tumour immune escape. Understanding the interactions between melanoma tumour cells and the immune system, and the evolving changes within the melanoma tumour cells, the immune system and the microenvironment, is essential for the development of new cancer therapies. However, current research suggests that other extrinsic factors, such as the microbiome, may play a role in the immune response to melanomas. Here, we review the mechanisms underlying the immune response in the tumour and discuss recent advances as well as strategies for treatment development., (© 2022. Springer Nature Limited.)
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- 2022
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26. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response.
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Spencer CN, McQuade JL, Gopalakrishnan V, McCulloch JA, Vetizou M, Cogdill AP, Khan MAW, Zhang X, White MG, Peterson CB, Wong MC, Morad G, Rodgers T, Badger JH, Helmink BA, Andrews MC, Rodrigues RR, Morgun A, Kim YS, Roszik J, Hoffman KL, Zheng J, Zhou Y, Medik YB, Kahn LM, Johnson S, Hudgens CW, Wani K, Gaudreau PO, Harris AL, Jamal MA, Baruch EN, Perez-Guijarro E, Day CP, Merlino G, Pazdrak B, Lochmann BS, Szczepaniak-Sloane RA, Arora R, Anderson J, Zobniw CM, Posada E, Sirmans E, Simon J, Haydu LE, Burton EM, Wang L, Dang M, Clise-Dwyer K, Schneider S, Chapman T, Anang NAS, Duncan S, Toker J, Malke JC, Glitza IC, Amaria RN, Tawbi HA, Diab A, Wong MK, Patel SP, Woodman SE, Davies MA, Ross MI, Gershenwald JE, Lee JE, Hwu P, Jensen V, Samuels Y, Straussman R, Ajami NJ, Nelson KC, Nezi L, Petrosino JF, Futreal PA, Lazar AJ, Hu J, Jenq RR, Tetzlaff MT, Yan Y, Garrett WS, Huttenhower C, Sharma P, Watowich SS, Allison JP, Cohen L, Trinchieri G, Daniel CR, and Wargo JA
- Subjects
- Animals, Cohort Studies, Fatty Acids, Volatile analysis, Fecal Microbiota Transplantation, Feces chemistry, Feces microbiology, Female, Humans, Immunotherapy, Male, Melanoma immunology, Melanoma microbiology, Melanoma, Experimental immunology, Melanoma, Experimental microbiology, Melanoma, Experimental therapy, Mice, Mice, Inbred C57BL, Progression-Free Survival, T-Lymphocytes, Dietary Fiber, Gastrointestinal Microbiome, Immune Checkpoint Inhibitors therapeutic use, Melanoma therapy, Probiotics
- Abstract
Gut bacteria modulate the response to immune checkpoint blockade (ICB) treatment in cancer, but the effect of diet and supplements on this interaction is not well studied. We assessed fecal microbiota profiles, dietary habits, and commercially available probiotic supplement use in melanoma patients and performed parallel preclinical studies. Higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use. Findings were recapitulated in preclinical models, which demonstrated impaired treatment response to anti–programmed cell death 1 (anti–PD-1)–based therapy in mice receiving a low-fiber diet or probiotics, with a lower frequency of interferon-γ–positive cytotoxic T cells in the tumor microenvironment. Together, these data have clinical implications for patients receiving ICB for cancer.
- Published
- 2021
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27. Combined presentation and immunogenicity analysis reveals a recurrent RAS.Q61K neoantigen in melanoma.
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Peri A, Greenstein E, Alon M, Pai JA, Dingjan T, Reich-Zeliger S, Barnea E, Barbolin C, Levy R, Arnedo-Pac C, Kalaora S, Dassa B, Feldmesser E, Shang P, Greenberg P, Levin Y, Benedek G, Levesque MP, Adams DJ, Lotem M, Wilmott JS, Scolyer RA, Jönsson GB, Admon A, Rosenberg SA, Cohen CJ, Niv MY, Lopez-Bigas N, Satpathy AT, Friedman N, and Samuels Y
- Subjects
- Cell Line, Tumor, HLA-A Antigens immunology, Humans, Lymphocytes, Tumor-Infiltrating immunology, Receptors, Antigen, T-Cell immunology, ras Proteins genetics, Antigens, Neoplasm immunology, Melanoma immunology, ras Proteins immunology
- Abstract
Neoantigens are now recognized drivers of the antitumor immune response. Recurrent neoantigens, shared among groups of patients, have thus become increasingly coveted therapeutic targets. Here, we report on the data-driven identification of a robustly presented, immunogenic neoantigen that is derived from the combination of HLA-A*01:01 and RAS.Q61K. Analysis of large patient cohorts indicated that this combination applies to 3% of patients with melanoma. Using HLA peptidomics, we were able to demonstrate robust endogenous presentation of the neoantigen in 10 tumor samples. We detected specific reactivity to the mutated peptide within tumor-infiltrating lymphocytes (TILs) from 2 unrelated patients, thus confirming its natural immunogenicity. We further investigated the neoantigen-specific clones and their T cell receptors (TCRs) via a combination of TCR sequencing, TCR overexpression, functional assays, and single-cell transcriptomics. Our analysis revealed a diverse repertoire of neoantigen-specific clones with both intra- and interpatient TCR similarities. Moreover, 1 dominant clone proved to cross-react with the highly prevalent RAS.Q61R variant. Transcriptome analysis revealed a high association of TCR clones with specific T cell phenotypes in response to cognate melanoma, with neoantigen-specific cells showing an activated and dysfunctional phenotype. Identification of recurrent neoantigens and their reactive TCRs can promote "off-the-shelf" precision immunotherapies, alleviating limitations of personalized treatments.
- Published
- 2021
- Full Text
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28. Identification of presented SARS-CoV-2 HLA class I and HLA class II peptides using HLA peptidomics.
- Author
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Nagler A, Kalaora S, Barbolin C, Gangaev A, Ketelaars SLC, Alon M, Pai J, Benedek G, Yahalom-Ronen Y, Erez N, Greenberg P, Yagel G, Peri A, Levin Y, Satpathy AT, Bar-Haim E, Paran N, Kvistborg P, and Samuels Y
- Subjects
- Antigen Presentation, Antigens, Viral metabolism, COVID-19 Vaccines, Cell Line, Epitopes, T-Lymphocyte immunology, HEK293 Cells, Histocompatibility Antigens Class I immunology, Histocompatibility Antigens Class II immunology, Humans, Peptidomimetics, SARS-CoV-2 genetics, T-Lymphocytes, Antigens, Viral immunology, COVID-19 immunology, COVID-19 virology, Peptides immunology, SARS-CoV-2 immunology
- Abstract
The human leukocyte antigen (HLA)-bound viral antigens serve as an immunological signature that can be selectively recognized by T cells. As viruses evolve by acquiring mutations, it is essential to identify a range of presented viral antigens. Using HLA peptidomics, we are able to identify severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides presented by highly prevalent HLA class I (HLA-I) molecules by using infected cells as well as overexpression of SARS-CoV-2 genes. We find 26 HLA-I peptides and 36 HLA class II (HLA-II) peptides. Among the identified peptides, some are shared between different cells and some are derived from out-of-frame open reading frames (ORFs). Seven of these peptides were previously shown to be immunogenic, and we identify two additional immunoreactive peptides by using HLA multimer staining. These results may aid the development of the next generation of SARS-CoV-2 vaccines based on presented viral-specific antigens that span several of the viral genes., Competing Interests: Declaration of interests Patent applications have been filed on SARS-CoV-2 peptides (Y.S., A.N., and S.K.). The remaining authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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29. Melanoma models for the next generation of therapies.
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Patton EE, Mueller KL, Adams DJ, Anandasabapathy N, Aplin AE, Bertolotto C, Bosenberg M, Ceol CJ, Burd CE, Chi P, Herlyn M, Holmen SL, Karreth FA, Kaufman CK, Khan S, Kobold S, Leucci E, Levy C, Lombard DB, Lund AW, Marie KL, Marine JC, Marais R, McMahon M, Robles-Espinoza CD, Ronai ZA, Samuels Y, Soengas MS, Villanueva J, Weeraratna AT, White RM, Yeh I, Zhu J, Zon LI, Hurlbert MS, and Merlino G
- Subjects
- Animals, Humans, Immunity immunology, Immunotherapy methods, Melanoma pathology, Skin Neoplasms pathology, Disease Models, Animal, Melanoma drug therapy, Skin Neoplasms drug therapy, Tumor Microenvironment immunology
- Abstract
There is a lack of appropriate melanoma models that can be used to evaluate the efficacy of novel therapeutic modalities. Here, we discuss the current state of the art of melanoma models including genetically engineered mouse, patient-derived xenograft, zebrafish, and ex vivo and in vitro models. We also identify five major challenges that can be addressed using such models, including metastasis and tumor dormancy, drug resistance, the melanoma immune response, and the impact of aging and environmental exposures on melanoma progression and drug resistance. Additionally, we discuss the opportunity for building models for rare subtypes of melanomas, which represent an unmet critical need. Finally, we identify key recommendations for melanoma models that may improve accuracy of preclinical testing and predict efficacy in clinical trials, to help usher in the next generation of melanoma therapies., Competing Interests: Declaration of interests D.J.A. is a paid consultant for Microbiotica and receives grant support from AstraZeneca and OpenTargets. N.A. is a consultant for Viela Bio. A.E.A. reports receiving a commercial research grant from Pfizer. (2013–2017) and has ownership interest in patent number 9880150. M.B. is a consultant for Eli Lilly and Company and Bristol-Myers Squibb. P.C. received grants and personal fees from Deciphera, personal fees from Exelixis, grants from Array/Pfizer, and personal fees from Zai lab. S. Khan has a US patent pending (62/654,025). S. Kobold received research support from TCR2 Inc and Arcus Bioscience for work unrelated to this manuscript, has licensed IP to TCR2 Inc, has received consultancy fees from TCR2 Inc and Novartis, and is an inventor of several patents and patent applications in the field of cancer immunotherapy. R.M. consults for Pfizer, and as a former employee of the Institute of Cancer Research he may benefit financially from drug-discovery programs that are commercialized. M.M. receives research funding from Pfizer and Deciphera Pharma; serves as a scientific advisor to Pfizer, Deciphera Pharma, Revolution Medicine, and ARO; and receives royalty income from the University of California for Braf(CA) mice, which are the basis of several GEM models of BRAF(V600E)-driven melanoma described in this review. Z.A.R. is founder and scientific advisor of Pangea Therapeutics. Y.S. is a consultant of Achilles Therapeutics Limited. A.T.W. sits on the advisory board for Melanoma Research Foundation, Phoremost Technologies, and Healthe Scientific. R.M.W. is a paid consultant to N-of-One Therapeutics, a subsidiary of Qiagen; is on the Scientific Advisory Board of Consano but receives no income for this; and receives royalty payments for the use of the casper line from Carolina Biologicals. L.I.Z. is a founder and stockholder of Fate Therapeutics, CAMP4 Therapeutics, and Scholar Rock, and a consultant for Celularity., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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30. Identification of bacteria-derived HLA-bound peptides in melanoma.
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Kalaora S, Nagler A, Nejman D, Alon M, Barbolin C, Barnea E, Ketelaars SLC, Cheng K, Vervier K, Shental N, Bussi Y, Rotkopf R, Levy R, Benedek G, Trabish S, Dadosh T, Levin-Zaidman S, Geller LT, Wang K, Greenberg P, Yagel G, Peri A, Fuks G, Bhardwaj N, Reuben A, Hermida L, Johnson SB, Galloway-Peña JR, Shropshire WC, Bernatchez C, Haymaker C, Arora R, Roitman L, Eilam R, Weinberger A, Lotan-Pompan M, Lotem M, Admon A, Levin Y, Lawley TD, Adams DJ, Levesque MP, Besser MJ, Schachter J, Golani O, Segal E, Geva-Zatorsky N, Ruppin E, Kvistborg P, Peterson SN, Wargo JA, Straussman R, and Samuels Y
- Subjects
- Antigen Presentation, Bacteria classification, Bacteria genetics, Cell Line, Tumor, Coculture Techniques, HLA Antigens analysis, Humans, Lymphocytes, Tumor-Infiltrating cytology, Lymphocytes, Tumor-Infiltrating immunology, Melanoma pathology, Neoplasm Metastasis immunology, Phylogeny, RNA, Ribosomal, 16S genetics, Antigens, Bacterial analysis, Antigens, Bacterial immunology, Bacteria immunology, HLA Antigens immunology, Melanoma immunology, Melanoma microbiology, Peptides analysis, Peptides immunology
- Abstract
A variety of species of bacteria are known to colonize human tumours
1-11 , proliferate within them and modulate immune function, which ultimately affects the survival of patients with cancer and their responses to treatment12-14 . However, it is not known whether antigens derived from intracellular bacteria are presented by the human leukocyte antigen class I and II (HLA-I and HLA-II, respectively) molecules of tumour cells, or whether such antigens elicit a tumour-infiltrating T cell immune response. Here we used 16S rRNA gene sequencing and HLA peptidomics to identify a peptide repertoire derived from intracellular bacteria that was presented on HLA-I and HLA-II molecules in melanoma tumours. Our analysis of 17 melanoma metastases (derived from 9 patients) revealed 248 and 35 unique HLA-I and HLA-II peptides, respectively, that were derived from 41 species of bacteria. We identified recurrent bacterial peptides in tumours from different patients, as well as in different tumours from the same patient. Our study reveals that peptides derived from intracellular bacteria can be presented by tumour cells and elicit immune reactivity, and thus provides insight into a mechanism by which bacteria influence activation of the immune system and responses to therapy.- Published
- 2021
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31. MEK Inhibition Reverses Aberrant Signaling in Melanoma Cells through Reorganization of NRas and BRAF in Self Nanoclusters.
- Author
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Yakovian O, Sajman J, Arafeh R, Neve-Oz Y, Alon M, Samuels Y, and Sherman E
- Subjects
- Cell Line, Tumor, Cell Membrane drug effects, Cell Membrane metabolism, Epidermal Growth Factor pharmacology, Extracellular Signal-Regulated MAP Kinases metabolism, GTP Phosphohydrolases genetics, Humans, MAP Kinase Kinase 1 antagonists & inhibitors, MAP Kinase Kinase 1 metabolism, Membrane Proteins genetics, Mutation, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins B-raf genetics, Pyridones pharmacology, Pyrimidinones pharmacology, Signal Transduction drug effects, Single Molecule Imaging, Melanoma, Cutaneous Malignant, GTP Phosphohydrolases metabolism, Melanoma drug therapy, Melanoma metabolism, Membrane Proteins metabolism, Proto-Oncogene Proteins B-raf metabolism, Skin Neoplasms drug therapy, Skin Neoplasms metabolism
- Abstract
Hotspot mutations of the oncogenes BRAF and NRas are the most common genetic alterations in cutaneous melanoma. Still, the nanoscale organization and signal coupling of these proteins remain incompletely understood, particularly upon expression of oncogenic NRas mutants. Here we employed single-molecule localization microscopy to study the nanoscale organization of NRas and BRAF at the plasma membrane (PM) of melanoma cells. NRas and BRAF resided in self-clusters that did not associate well in resting cells. In EGF-activated cells, NRas clusters became more diffused while overall protein levels at the PM increased; thus allowing enhanced association of NRas and BRAF and downstream signaling. In multiple melanoma cell lines, mutant NRas resided in more pronounced self-clusters relative to wild-type (WT) NRas yet associated more with the clustered and more abundant BRAF. In cells resistant to trametinib, a clinical MEK inhibitor (MEKi), a similar coclustering of NRas and BRAF was observed upon EGF activation. Strikingly, treatment of cells expressing mutant NRas with trametinib reversed the effect of mutant NRas expression by restoring the nonoverlapping self-clusters of NRas and BRAF and by reducing their PM levels and elevated pERK levels caused by mutant NRas. Our results indicate a new mechanism for signal regulation of NRas in melanoma through its nanoscale dynamic organization and a new mechanism for MEKi function in melanoma cells carrying NRas mutations but lacking MEK mutations. SIGNIFICANCE: Nanoscale dynamic organization of WT and mutant NRas relative to BRAF serves as a regulatory mechanism for NRas signaling and may be a viable therapeutic target for its sensitivity to MEKi., (©2020 American Association for Cancer Research.)
- Published
- 2021
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32. Anti-tumour immunity induces aberrant peptide presentation in melanoma.
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Bartok O, Pataskar A, Nagel R, Laos M, Goldfarb E, Hayoun D, Levy R, Körner PR, Kreuger IZM, Champagne J, Zaal EA, Bleijerveld OB, Huang X, Kenski J, Wargo J, Brandis A, Levin Y, Mizrahi O, Alon M, Lebon S, Yang W, Nielsen MM, Stern-Ginossar N, Altelaar M, Berkers CR, Geiger T, Peeper DS, Olweus J, Samuels Y, and Agami R
- Subjects
- Cell Line, Codon genetics, Frameshifting, Ribosomal drug effects, Frameshifting, Ribosomal genetics, Frameshifting, Ribosomal immunology, Histocompatibility Antigens Class I immunology, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase antagonists & inhibitors, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Interferon-gamma immunology, Interferon-gamma pharmacology, Melanoma pathology, Peptides chemistry, Protein Biosynthesis drug effects, Protein Biosynthesis genetics, Proteome, Ribosomes drug effects, Ribosomes metabolism, Tryptophan deficiency, Tryptophan genetics, Tryptophan metabolism, Antigen Presentation, Frameshift Mutation, Melanoma immunology, Peptides genetics, Peptides immunology, Protein Biosynthesis immunology, T-Lymphocytes immunology
- Abstract
Extensive tumour inflammation, which is reflected by high levels of infiltrating T cells and interferon-γ (IFNγ) signalling, improves the response of patients with melanoma to checkpoint immunotherapy
1,2 . Many tumours, however, escape by activating cellular pathways that lead to immunosuppression. One such mechanism is the production of tryptophan metabolites along the kynurenine pathway by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which is induced by IFNγ3-5 . However, clinical trials using inhibition of IDO1 in combination with blockade of the PD1 pathway in patients with melanoma did not improve the efficacy of treatment compared to PD1 pathway blockade alone6,7 , pointing to an incomplete understanding of the role of IDO1 and the consequent degradation of tryptophan in mRNA translation and cancer progression. Here we used ribosome profiling in melanoma cells to investigate the effects of prolonged IFNγ treatment on mRNA translation. Notably, we observed accumulations of ribosomes downstream of tryptophan codons, along with their expected stalling at the tryptophan codon. This suggested that ribosomes bypass tryptophan codons in the absence of tryptophan. A detailed examination of these tryptophan-associated accumulations of ribosomes-which we term 'W-bumps'-showed that they were characterized by ribosomal frameshifting events. Consistently, reporter assays combined with proteomic and immunopeptidomic analyses demonstrated the induction of ribosomal frameshifting, and the generation and presentation of aberrant trans-frame peptides at the cell surface after treatment with IFNγ. Priming of naive T cells from healthy donors with aberrant peptides induced peptide-specific T cells. Together, our results suggest that IDO1-mediated depletion of tryptophan, which is induced by IFNγ, has a role in the immune recognition of melanoma cells by contributing to diversification of the peptidome landscape.- Published
- 2021
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33. PhISCS-BnB: a fast branch and bound algorithm for the perfect tumor phylogeny reconstruction problem.
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Sadeqi Azer E, Rashidi Mehrabadi F, Malikić S, Li XC, Bartok O, Litchfield K, Levy R, Samuels Y, Schäffer AA, Gertz EM, Day CP, Pérez-Guijarro E, Marie K, Lee MP, Merlino G, Ergun F, and Sahinalp SC
- Subjects
- Humans, Markov Chains, Phylogeny, Sequence Analysis, Software, Algorithms, Neoplasms genetics
- Abstract
Motivation: Recent advances in single-cell sequencing (SCS) offer an unprecedented insight into tumor emergence and evolution. Principled approaches to tumor phylogeny reconstruction via SCS data are typically based on general computational methods for solving an integer linear program, or a constraint satisfaction program, which, although guaranteeing convergence to the most likely solution, are very slow. Others based on Monte Carlo Markov Chain or alternative heuristics not only offer no such guarantee, but also are not faster in practice. As a result, novel methods that can scale up to handle the size and noise characteristics of emerging SCS data are highly desirable to fully utilize this technology., Results: We introduce PhISCS-BnB (phylogeny inference using SCS via branch and bound), a branch and bound algorithm to compute the most likely perfect phylogeny on an input genotype matrix extracted from an SCS dataset. PhISCS-BnB not only offers an optimality guarantee, but is also 10-100 times faster than the best available methods on simulated tumor SCS data. We also applied PhISCS-BnB on a recently published large melanoma dataset derived from the sublineages of a cell line involving 20 clones with 2367 mutations, which returned the optimal tumor phylogeny in <4 h. The resulting phylogeny agrees with and extends the published results by providing a more detailed picture on the clonal evolution of the tumor., Availability and Implementation: https://github.com/algo-cancer/PhISCS-BnB., Supplementary Information: Supplementary data are available at Bioinformatics online., (Published by Oxford University Press 2020.)
- Published
- 2020
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34. A genome-wide CRISPR screen identifies FBXO42 involvement in resistance toward MEK inhibition in NRAS-mutant melanoma.
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Nagler A, Vredevoogd DW, Alon M, Cheng PF, Trabish S, Kalaora S, Arafeh R, Goldin V, Levesque MP, Peeper DS, and Samuels Y
- Subjects
- Base Sequence, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, CRISPR-Cas Systems genetics, Cell Line, Tumor, Genetic Testing, Humans, MAP Kinase Kinase Kinases metabolism, MAP Kinase Signaling System drug effects, MAP Kinase Signaling System genetics, Melanoma drug therapy, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Models, Biological, Mutation genetics, Protein Binding drug effects, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Pyridones pharmacology, Pyridones therapeutic use, Pyrimidinones pharmacology, Pyrimidinones therapeutic use, Skin Neoplasms drug therapy, Drug Resistance, Neoplasm genetics, F-Box Proteins genetics, F-Box Proteins metabolism, GTP Phosphohydrolases genetics, Genome, Human, Melanoma genetics, Membrane Proteins genetics, Skin Neoplasms genetics
- Abstract
NRAS mutations are the most common alterations among RAS isoforms in cutaneous melanoma, with patients harboring these aggressive tumors having a poor prognosis and low survival rate. The main line of treatment for these patients is MAPK pathway-targeted therapies, such as MEK inhibitors, but, unfortunately, the response to these inhibitors is variable due to tumor resistance. Identifying genetic modifiers involved in resistance toward MEK-targeted therapy may assist in the development of new therapeutic strategies, enhancing treatment response and patient survival. Our whole-genome CRISPR-Cas9 knockout screen identified the target Kelch domain-containing F-Box protein 42 (FBXO42) as a factor involved in NRAS-mutant melanoma-acquired resistance to the MEK1/2 inhibitor trametinib. We further show that FBXO42, an E3 ubiquitin ligase, is involved in the TAK1 signaling pathway, possibly prompting an increase in active P38. In addition, we demonstrate that combining trametinib with the TAK1 inhibitor, takinib, is a far more efficient treatment than trametinib alone in NRAS-mutant melanoma cells. Our findings thus show a new pathway involved in NRAS-mutant melanoma resistance and provide new opportunities for novel therapeutic options., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2020
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35. Immunoproteasome expression is associated with better prognosis and response to checkpoint therapies in melanoma.
- Author
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Kalaora S, Lee JS, Barnea E, Levy R, Greenberg P, Alon M, Yagel G, Bar Eli G, Oren R, Peri A, Patkar S, Bitton L, Rosenberg SA, Lotem M, Levin Y, Admon A, Ruppin E, and Samuels Y
- Subjects
- Antigen Presentation, Cysteine Endopeptidases genetics, Cysteine Endopeptidases immunology, Humans, Immunotherapy, Interferon-gamma genetics, Interferon-gamma immunology, Melanoma diagnosis, Melanoma genetics, Prognosis, Proteasome Endopeptidase Complex immunology, Melanoma immunology, Melanoma therapy, Proteasome Endopeptidase Complex genetics
- Abstract
Predicting the outcome of immunotherapy treatment in melanoma patients is challenging. Alterations in genes involved in antigen presentation and the interferon gamma (IFNγ) pathway play an important role in the immune response to tumors. We describe here that the overexpression of PSMB8 and PSMB9, two major components of the immunoproteasome, is predictive of better survival and improved response to immune-checkpoint inhibitors of melanoma patients. We study the mechanism underlying this connection by analyzing the antigenic peptide repertoire of cells that overexpress these subunits using HLA peptidomics. We find a higher response of patient-matched tumor infiltrating lymphocytes against antigens diferentially presented after immunoproteasome overexpression. Importantly, we find that PSMB8 and PSMB9 expression levels are much stronger predictors of melanoma patients' immune response to checkpoint inhibitors than the tumors' mutational burden. These results suggest that PSMB8 and PSMB9 expression levels can serve as important biomarkers for stratifying melanoma patients for immune-checkpoint treatment.
- Published
- 2020
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36. PIK3CA in cancer: The past 30 years.
- Author
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Arafeh R and Samuels Y
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors, Gain of Function Mutation, Humans, Molecular Targeted Therapy, Mutation, Neoplasms drug therapy, Neoplasms pathology, Phosphoinositide-3 Kinase Inhibitors pharmacology, Phosphoinositide-3 Kinase Inhibitors therapeutic use, Class I Phosphatidylinositol 3-Kinases genetics, Class I Phosphatidylinositol 3-Kinases metabolism, Neoplasms etiology, Neoplasms metabolism
- Abstract
Almost thirty years ago, PI3K was discovered as a lipid kinase associated with certain oncoproteins. The first decade of research on PI3K saw the identification, purification and cloning of PI3Kα. The second decade of research was noted for the identification of some of PI3K's activators and effectors. This was accompanied by the discovery that PI3K acts as a retroviral oncogene. The third decade was known for the establishment of the direct involvement of PI3K in cancer, demonstrated by the identification of cancer-specific mutations. Efforts to target PI3K were on the rise from that moment on, accompanied by the first clinical trials for PI3K inhibitor therapies. In the fourth decade of research, PI3K-based cancer drugs will continue to emerge, as will new knowledge regarding other uncovered functions of this protein and pathway., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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37. UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma.
- Author
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Wolf Y, Bartok O, Patkar S, Eli GB, Cohen S, Litchfield K, Levy R, Jiménez-Sánchez A, Trabish S, Lee JS, Karathia H, Barnea E, Day CP, Cinnamon E, Stein I, Solomon A, Bitton L, Pérez-Guijarro E, Dubovik T, Shen-Orr SS, Miller ML, Merlino G, Levin Y, Pikarsky E, Eisenbach L, Admon A, Swanton C, Ruppin E, and Samuels Y
- Subjects
- Animals, Carcinogenesis genetics, Cell Line, Tumor, Cohort Studies, Disease Models, Animal, Female, Humans, Lymphocytes, Tumor-Infiltrating, Melanoma mortality, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mutation radiation effects, Phylogeny, Skin Neoplasms mortality, Survival Rate, T-Lymphocytes immunology, Tumor Microenvironment immunology, Tumor Microenvironment radiation effects, Genetic Heterogeneity radiation effects, Melanoma genetics, Melanoma immunology, Skin Neoplasms genetics, Skin Neoplasms immunology, Ultraviolet Rays adverse effects
- Abstract
Although clonal neo-antigen burden is associated with improved response to immune therapy, the functional basis for this remains unclear. Here we study this question in a novel controlled mouse melanoma model that enables us to explore the effects of intra-tumor heterogeneity (ITH) on tumor aggressiveness and immunity independent of tumor mutational burden. Induction of UVB-derived mutations yields highly aggressive tumors with decreased anti-tumor activity. However, single-cell-derived tumors with reduced ITH are swiftly rejected. Their rejection is accompanied by increased T cell reactivity and a less suppressive microenvironment. Using phylogenetic analyses and mixing experiments of single-cell clones, we dissect two characteristics of ITH: the number of clones forming the tumor and their clonal diversity. Our analysis of melanoma patient tumor data recapitulates our results in terms of overall survival and response to immune checkpoint therapy. These findings highlight the importance of clonal mutations in robust immune surveillance and the need to quantify patient ITH to determine the response to checkpoint blockade., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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38. Exome Sequencing of ABCB5 Identifies Recurrent Melanoma Mutations that Result in Increased Proliferative and Invasive Capacities.
- Author
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Sana G, Madigan JP, Gartner JJ, Fourrez M, Lin J, Qutob N, Narayan J, Shukla S, Ambudkar SV, Xia D, Rosenberg SA, Gottesman MM, Samuels Y, and Gillet JP
- Subjects
- ATP Binding Cassette Transporter, Subfamily B metabolism, Adenosine Triphosphate metabolism, Adult, Cell Line, Tumor, Cell Movement genetics, Cell Proliferation genetics, Cyclin-Dependent Kinase Inhibitor p16 genetics, DNA Mutational Analysis, Female, GTP Phosphohydrolases genetics, Humans, Hydrolysis, Male, Melanoma pathology, Membrane Proteins genetics, Middle Aged, Mutation, Skin pathology, Skin Neoplasms pathology, Exome Sequencing, Young Adult, ATP Binding Cassette Transporter, Subfamily B genetics, Genes, Tumor Suppressor, Melanoma genetics, Skin Neoplasms genetics
- Abstract
ABCB5 is an ABC transporter that was shown to confer low-level multidrug resistance in cancer. In this study, we show that ABCB5 was mutated in 13.75% of the 640 melanoma samples analyzed. Besides nonsense mutations, two mutation hotspots were found in the ABCB5 protein, in the drug-binding pocket and the nucleotide-binding domains. Four mutations, which are representative of the mutation pattern, were selected. ATPase assays showed that these mutations resulted in a decrease in basal ATP hydrolysis by ABCB5. To select informative melanoma cell lines, mutational profiles of the clinical samples were further analyzed. This study showed mutations in the tumor suppressor CDKN2A gene and the NRAS oncogene in 62.5% and 75%, respectively of the samples that had mutations in the ABCB5 gene. No mutation was found in the tumor suppressor PTEN gene, whereas the activating V600E mutation in the BRAF oncogene was found in 25% of the samples with a mutated ABCB5 gene. Studies in four melanoma cell lines with various genetic backgrounds showed an increase in the proliferation and migration capacity of mutant ABCB5-expressing cells, suggesting that ABCB5 plays a role in the development of melanoma as a tumor suppressor gene., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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39. Cross-Talk between Receptor Tyrosine Kinases AXL and ERBB3 Regulates Invadopodia Formation in Melanoma Cells.
- Author
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Revach OY, Sandler O, Samuels Y, and Geiger B
- Subjects
- Actins metabolism, Cell Adhesion Molecules metabolism, Cell Line, Cell Line, Tumor, Extracellular Matrix metabolism, Extracellular Matrix pathology, HEK293 Cells, Humans, Neoplasm Invasiveness pathology, Signal Transduction physiology, Up-Regulation physiology, Axl Receptor Tyrosine Kinase, Melanoma metabolism, Melanoma pathology, Podosomes metabolism, Podosomes pathology, Proto-Oncogene Proteins metabolism, Receptor Protein-Tyrosine Kinases metabolism, Receptor, ErbB-3 metabolism
- Abstract
The invasive phenotype of metastatic cancer cells is accompanied by the formation of actin-rich invadopodia, which adhere to the extracellular matrix and degrade it. In this study, we explored the role of the tyrosine kinome in the formation of invadopodia in metastatic melanoma cells. Using a microscopy-based siRNA screen, we identified a series of regulators, the knockdown of which either suppresses (e.g., TYK2, IGFR1, ERBB3, TYRO3, FES, ALK, PTK7) or enhances (e.g., ABL2, AXL, CSK) invadopodia formation and function. Notably, the receptor tyrosine kinase AXL displayed a dual regulatory function, where both depletion or overexpression enhanced invadopodia formation and activity. This apparent contradiction was attributed to the capacity of AXL to directly stimulate invadopodia, yet its suppression upregulates the ERBB3 signaling pathway, which can also activate core invadopodia regulators and enhance invadopodia function. Bioinformatic analysis of multiple melanoma cell lines points to an inverse expression pattern of AXL and ERBB3. High expression of AXL in melanoma cells is associated with high expression of invadopodia components and an invasive phenotype. These results provide new insights into the complexity of metastasis-promoting mechanisms and suggest that targeting of multiple invadopodia signaling networks may serve as a potential anti-invasion therapy in melanoma. SIGNIFICANCE: These findings uncover a unique interplay between AXL and ERBB3 in invadopodia regulation that points to the need for combined therapy in order to prevent invadopodia-mediated metastasis in melanoma., (©2019 American Association for Cancer Research.)
- Published
- 2019
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40. Author Correction: Combined inhibition of MEK and nuclear ERK translocation has synergistic antitumor activity in melanoma cells.
- Author
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Arafeh R, Flores K, Keren-Paz A, Maik-Rachline G, Gutkind N, Rosenberg S, Seger R, and Samuels Y
- Abstract
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
- Published
- 2019
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41. Author Correction: RGS7 is recurrently mutated in melanoma and promotes migration and invasion of human cancer cells.
- Author
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Qutob N, Masuho I, Alon M, Emmanuel R, Cohen I, Di Pizio A, Madore J, Elkahloun A, Ziv T, Levy R, Gartner JJ, Hill VK, Lin JC, Hevroni Y, Greenberg P, Brodezki A, Rosenberg SA, Kosloff M, Hayward NK, Admon A, Niv MY, Scolyer RA, Martemyanov KA, and Samuels Y
- Abstract
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
- Published
- 2019
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42. RASA2 and NF1; two-negative regulators of Ras with complementary functions in melanoma.
- Author
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Arafeh R, Di Pizio A, Elkahloun AG, Dym O, Niv MY, and Samuels Y
- Subjects
- Animals, Humans, Melanoma metabolism, Neurofibromin 1 metabolism, ras GTPase-Activating Proteins metabolism, ras Proteins metabolism
- Published
- 2019
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43. Correction: CAPN1 is a novel binding partner and regulator of the tumor suppressor NF1 in melanoma.
- Author
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Alon M, Arafeh R, Lee JS, Madan S, Kalaora S, Nagler A, Abgarian T, Greenberg P, Ruppin E, and Samuels Y
- Abstract
[This corrects the article DOI: 10.18632/oncotarget.25805.].
- Published
- 2019
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44. Cancer Exome-Based Identification of Tumor Neo-Antigens Using Mass Spectrometry.
- Author
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Kalaora S and Samuels Y
- Subjects
- Algorithms, Antigens, Neoplasm genetics, Antigens, Neoplasm immunology, Cell Culture Techniques instrumentation, Cell Culture Techniques methods, Chromatography, High Pressure Liquid instrumentation, Chromatography, High Pressure Liquid methods, Exome genetics, Histocompatibility Antigens Class I genetics, Histocompatibility Antigens Class I immunology, Histocompatibility Antigens Class I isolation & purification, Histocompatibility Antigens Class II genetics, Histocompatibility Antigens Class II immunology, Histocompatibility Antigens Class II isolation & purification, Humans, Hybridomas, Immunoprecipitation instrumentation, Immunoprecipitation methods, Neoplasms pathology, Proteomics instrumentation, Spectrometry, Mass, Electrospray Ionization instrumentation, Spectrometry, Mass, Electrospray Ionization methods, Tandem Mass Spectrometry instrumentation, Antigens, Neoplasm isolation & purification, Exome immunology, Neoplasms immunology, Proteomics methods, Tandem Mass Spectrometry methods
- Abstract
Neo-antigens expressed on tumors are targets for development of cancer immunotherapy strategies. Use of prediction algorithms to identify neo-antigens yields a significant number of peptides that must be validated in laborious and time-consuming methods; many prove to be false-positive identifications. The use of HLA peptidomics allows the isolation of the HLA-peptide complexes directly from cells and can be done on fresh tumor, patient-derived xerographs, or cell lines when the tissue sample is limited. This method can be used to identify both HLA class I and HLA class II or any different MHC from different species. Here we describe the steps to create the immune-affinity columns used from the process, the immunoprecipitation procedure, and also the isolation of the peptides that will be analyzed by mass spectrometry.
- Published
- 2019
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45. Cancer research in the era of immunogenomics.
- Author
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Wolf Y and Samuels Y
- Abstract
The most meaningful advancement in cancer treatment in recent years has been the emergence of immunotherapy. Checkpoint inhibitor blockade and adoptive T cell therapy have shown remarkable clinical effects in a wide range of tumour types. Despite these advances, many tumours do not respond to these treatments, which raises the need to further investigate how patients can benefit from immunotherapy. This effort can now take advantage of the recent technological progress in single-cell, high-throughput sequencing and computational efforts. In this review, we will discuss advances in different immunotherapies and the principles of cancer immunogenomics, with an emphasis on the detection of cancer neoantigens with human leucocyte antigen peptidomics, and how these principles can be further used for more efficient clinical output., Competing Interests: Competing interests: None declared.
- Published
- 2018
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46. Combined Analysis of Antigen Presentation and T-cell Recognition Reveals Restricted Immune Responses in Melanoma.
- Author
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Kalaora S, Wolf Y, Feferman T, Barnea E, Greenstein E, Reshef D, Tirosh I, Reuben A, Patkar S, Levy R, Quinkhardt J, Omokoko T, Qutob N, Golani O, Zhang J, Mao X, Song X, Bernatchez C, Haymaker C, Forget MA, Creasy C, Greenberg P, Carter BW, Cooper ZA, Rosenberg SA, Lotem M, Sahin U, Shakhar G, Ruppin E, Wargo JA, Friedman N, Admon A, and Samuels Y
- Subjects
- Animals, Antigens, Neoplasm metabolism, Histocompatibility Antigens Class I metabolism, Humans, Melanoma metabolism, Melanoma pathology, Mice, Mice, Inbred NOD, Mice, SCID, T-Lymphocytes metabolism, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Antigen Presentation immunology, Antigens, Neoplasm immunology, Histocompatibility Antigens Class I immunology, Lymphocytes, Tumor-Infiltrating immunology, Melanoma immunology, T-Lymphocytes immunology
- Abstract
The quest for tumor-associated antigens (TAA) and neoantigens is a major focus of cancer immunotherapy. Here, we combine a neoantigen prediction pipeline and human leukocyte antigen (HLA) peptidomics to identify TAAs and neoantigens in 16 tumors derived from seven patients with melanoma and characterize their interactions with their tumor-infiltrating lymphocytes (TIL). Our investigation of the antigenic and T-cell landscapes encompassing the TAA and neoantigen signatures, their immune reactivity, and their corresponding T-cell identities provides the first comprehensive analysis of cancer cell T-cell cosignatures, allowing us to discover remarkable antigenic and TIL similarities between metastases from the same patient. Furthermore, we reveal that two neoantigen-specific clonotypes killed 90% of autologous melanoma cells, both in vitro and in vivo , showing that a limited set of neoantigen-specific T cells may play a central role in melanoma tumor rejection. Our findings indicate that combining HLA peptidomics with neoantigen predictions allows robust identification of targetable neoantigens, which could successfully guide personalized cancer immunotherapies. Significance: As neoantigen targeting is becoming more established as a powerful therapeutic approach, investigating these molecules has taken center stage. Here, we show that a limited set of neoantigen-specific T cells mediates tumor rejection, suggesting that identifying just a few antigens and their corresponding T-cell clones could guide personalized immunotherapy. Cancer Discov; 8(11); 1366-75. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333 ., (©2018 American Association for Cancer Research.)
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- 2018
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47. Mutated MITF-E87R in Melanoma Enhances Tumor Progression via S100A4.
- Author
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Nordlinger A, Dror S, Elkahloun A, Del Rio J, Stubbs E, Golan T, Malcov H, Pricket TD, Cronin JC, Parikh S, Labes S, Thomas L, Yankovitz G, Tabach Y, Levy C, Samuels Y, and Khaled M
- Subjects
- DNA Mutational Analysis, Disease Progression, Humans, Immunoblotting, Melanoma metabolism, Melanoma pathology, Microphthalmia-Associated Transcription Factor metabolism, S100 Calcium-Binding Protein A4 biosynthesis, Skin Neoplasms metabolism, Skin Neoplasms pathology, Tumor Cells, Cultured, DNA, Neoplasm genetics, Gene Expression Regulation, Neoplastic, Melanoma genetics, Microphthalmia-Associated Transcription Factor genetics, Mutation, S100 Calcium-Binding Protein A4 genetics, Skin Neoplasms genetics
- Abstract
Melanoma, a melanocyte origin neoplasm, is the most lethal type of skin cancer, and incidence is increasing. Several familial and somatic mutations have been identified in the gene encoding the melanocyte lineage master regulator, MITF; however, the neoplastic mechanisms of these mutant MITF variants are mostly unknown. Here, by performing unbiased analysis of the transcriptomes in cells expressing mutant MITF, we identified calcium-binding protein S100A4 as a downstream target of MITF-E87R. By using wild-type and mutant MITF melanoma lines, we found that both endogenous wild-type and MITF-E87R variants occupy the S100A4 promoter. Remarkably, whereas wild-type MITF represses S100A4 expression, MITF-E87R activates its transcription. The opposite effects of wild-type and mutant MITF result in opposing cellular phenotypes, because MITF-E87R via S100A4 enhanced invasion and reduced adhesion in contrast to wild-type MITF activity. Finally, we found that melanoma patients with altered S100A4 expression have poor prognosis. These data show that a change in MITF transcriptional activity from repression to activation of S100A4 that results from a point mutation in MITF alters melanoma invasive ability. These data suggest new opportunities for diagnosis and treatment of metastatic melanoma., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2018
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48. Urea Cycle Dysregulation Generates Clinically Relevant Genomic and Biochemical Signatures.
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Lee JS, Adler L, Karathia H, Carmel N, Rabinovich S, Auslander N, Keshet R, Stettner N, Silberman A, Agemy L, Helbling D, Eilam R, Sun Q, Brandis A, Malitsky S, Itkin M, Weiss H, Pinto S, Kalaora S, Levy R, Barnea E, Admon A, Dimmock D, Stern-Ginossar N, Scherz A, Nagamani SCS, Unda M, Wilson DM 3rd, Elhasid R, Carracedo A, Samuels Y, Hannenhalli S, Ruppin E, and Erez A
- Subjects
- Amino Acid Transport Systems, Basic metabolism, Animals, Aspartate Carbamoyltransferase genetics, Aspartate Carbamoyltransferase metabolism, Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) genetics, Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) metabolism, Cell Line, Tumor, Dihydroorotase genetics, Dihydroorotase metabolism, Female, Humans, Mice, Mice, Inbred C57BL, Mice, SCID, Mitochondrial Membrane Transport Proteins, Neoplasms metabolism, Ornithine Carbamoyltransferase antagonists & inhibitors, Ornithine Carbamoyltransferase genetics, Ornithine Carbamoyltransferase metabolism, Phosphorylation drug effects, Pyrimidines biosynthesis, Pyrimidines chemistry, RNA Interference, RNA, Small Interfering metabolism, Sirolimus pharmacology, TOR Serine-Threonine Kinases antagonists & inhibitors, TOR Serine-Threonine Kinases metabolism, Genomics, Metabolomics, Neoplasms pathology, Urea metabolism
- Abstract
The urea cycle (UC) is the main pathway by which mammals dispose of waste nitrogen. We find that specific alterations in the expression of most UC enzymes occur in many tumors, leading to a general metabolic hallmark termed "UC dysregulation" (UCD). UCD elicits nitrogen diversion toward carbamoyl-phosphate synthetase2, aspartate transcarbamylase, and dihydrooratase (CAD) activation and enhances pyrimidine synthesis, resulting in detectable changes in nitrogen metabolites in both patient tumors and their bio-fluids. The accompanying excess of pyrimidine versus purine nucleotides results in a genomic signature consisting of transversion mutations at the DNA, RNA, and protein levels. This mutational bias is associated with increased numbers of hydrophobic tumor antigens and a better response to immune checkpoint inhibitors independent of mutational load. Taken together, our findings demonstrate that UCD is a common feature of tumors that profoundly affects carcinogenesis, mutagenesis, and immunotherapy response., (Copyright © 2018 Elsevier Inc. All rights reserved.)
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- 2018
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49. Refinement of the endogenous epitope tagging technology allows the identification of a novel NRAS binding partner in melanoma.
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Alon M, Emmanuel R, Qutob N, Bakhman A, Peshti V, Brodezki A, Bassan D, Kosloff M, and Samuels Y
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- Epitopes genetics, GTP Phosphohydrolases genetics, Humans, Melanoma genetics, Melanoma pathology, Membrane Proteins genetics, Mutation, Protein Interaction Domains and Motifs, Proto-Oncogene Proteins c-cbl genetics, Tumor Cells, Cultured, Epitope Mapping methods, Epitopes metabolism, GTP Phosphohydrolases metabolism, Melanoma metabolism, Membrane Proteins metabolism, Proteomics methods, Proto-Oncogene Proteins c-cbl metabolism
- Abstract
The NRAS oncoprotein is highly mutated in melanoma. However, to date, no comprehensive proteomic study has been reported for NRAS. Here, we utilized the endogenous epitope tagging (EET) approach for the identification of novel NRAS binding partners. Using EET, an epitope tag is added to the endogenously expressed protein, via modification of its genomic coding sequence. Existing EET systems are not robust, suffer from high background, and are labor-intensive. To this end, we present a polyadenylation signal-trap construct for N'-tagging that generates a polycistronic mRNA with the gene of interest. This system requires the integration of the tagging cassette in frame with the target gene to be expressed. Using this design, we demonstrate, for the first time, endogenous tagging of NRAS in melanoma cells allowing the identification of the E3 ubiquitin ligase c-CBL as a novel NRAS binding partner. Thus, our developed EET technology allows the characterization of new RAS effectors, which could be beneficial for the design of future drugs that inhibit constitutive signaling of RAS oncogenic mutants., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2018
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50. CAPN1 is a novel binding partner and regulator of the tumor suppressor NF1 in melanoma.
- Author
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Alon M, Arafeh R, Lee JS, Madan S, Kalaora S, Nagler A, Abgarian T, Greenberg P, Ruppin E, and Samuels Y
- Abstract
Neurofibromin 1 (NF1), a tumor suppressor that negatively regulates RAS through its GTPase activity, is highly mutated in various types of sporadic human cancers, including melanoma. However, the binding partners of NF1 and the pathways in which it is involved in melanoma have not been characterized in an in depth manner. Utilizing a mass spectrometry analysis of NF1 binding partners, we revealed Calpain1 (CAPN1), a calcium-dependent neutral cysteine protease, as a novel NF1 binding partner that regulates NF1 degradation in melanoma cells. ShRNA-mediated knockdown of CAPN1 or treatment with a CAPN1 inhibitor stabilizes NF1 protein levels, downregulates AKT signaling and melanoma cell growth. Combination treatment of Calpain inhibitor I with MEKi Trametinib in different melanoma cells is more effective in reducing melanoma cell growth compared to treatment with Trametinib alone, suggesting that this combination may have a therapeutic potential in melanoma. This novel mechanism for regulating NF1 in melanoma provides a molecular basis for targeting CAPN1 in order to stabilize NF1 levels and, in doing so, suppressing Ras activation; this mechanism can be exploited therapeutically in melanoma and other cancers., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no competing interest.
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- 2018
- Full Text
- View/download PDF
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