46 results on '"Oricchio E"'
Search Results
2. P1290: A TISSUE-BASED EX VIVO CULTURE SYSTEM TO ANTICIPATE TEHRAPY RESPONSE IN LYMPHOMA.
- Author
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Santamaria-Martínez, A., primary, Epiney, J., additional, Srivastava, D., additional, Tavernari, D., additional, Milowich, D., additional, Letovanec, I., additional, Ciriello, G., additional, Cairoli, A., additional, and Oricchio, E., additional
- Published
- 2022
- Full Text
- View/download PDF
3. Distinct roles for LINE-1 and HERV-K retroelements in cell proliferation, differentiation and tumor progression
- Author
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Oricchio, E, Sciamanna, I, Beraldi, R, Tolstonog, G V, Schumann, G G, and Spadafora, C
- Published
- 2007
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4. The activation of human endogenous retrovirus K (HERV-K) is implicated in melanoma cell malignant transformation
- Author
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Serafino, A., Balestrieri, E., Pierimarchi, P., Matteucci, C., Moroni, G., Oricchio, E., Rasi, G., Mastino, A., Spadafora, C., Garaci, E., and Vallebona, Sinibaldi P.
- Published
- 2009
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5. Interrogating functional dependencies between genomic alterations can facilitate precision medicine approaches in cancer
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Mina, M., primary, Raynaud, F., additional, Tavernari, D., additional, Battistello, E., additional, Sungalee, S., additional, Saghafinia, S., additional, Laessle, T., additional, Sanchez-Vega, F., additional, Schultz, N., additional, Oricchio, E., additional, and Ciriello, G., additional
- Published
- 2017
- Full Text
- View/download PDF
6. LYMPHOMA TISSUE EXPLANTS TO ANTICIPATE RESPONSE TO TARGETED THERAPIES.
- Author
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Santamaria‐Martínez, A., Epiney, J., Srivastava, D., Tavernari, D., Varrone, M., Milowich, D., Letovanec, I., Krueger, T., Duran, R., Ciriello, G., Cairoli, A., and Oricchio, E.
- Subjects
LYMPHOMAS ,TREATMENT effectiveness ,DNA fingerprinting ,TISSUES - Abstract
All in all, lymphomoids represent an innovative tool to assess therapy response in lymphoma patients and uncover novel aspects of lymphoma biology. As they retained histological, cellular, and molecular characteristics distinctive of the original tissue, we called them I lymphomoids. i To anticipate sensitivity to anti-cancer therapies, we tested response to targeted therapies on lymphomoids obtained from human primary lymphomas. [Extracted from the article]
- Published
- 2023
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7. I retroelementi nella tumorigenesi: ruoli distinti di LINE-1 ed HERV-K nella progressione tumorale
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Oricchio, E
- Subjects
retroelements ,proliferation ,differentiation ,tumorigenesis ,retroelementi ,proliferazione cellulare ,tumorigenesi ,differenziamento ,Settore MED/07 - Microbiologia e Microbiologia Clinica - Published
- 2008
8. 4 - Interrogating functional dependencies between genomic alterations can facilitate precision medicine approaches in cancer
- Author
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Mina, M., Raynaud, F., Tavernari, D., Battistello, E., Sungalee, S., Saghafinia, S., Laessle, T., Sanchez-Vega, F., Schultz, N., Oricchio, E., and Ciriello, G.
- Published
- 2017
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9. Stress da bassa concentrazione di siero induce attivazione di Human Endogenous Retrovirus-k in cellule di melanoma umano
- Author
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Serafino A.a, Balestrieri E., Pierimarchi P.b, Matteucci C.c, Moroni G., Oricchio E., Sorrentino R., Mastino A., Garaci E.d, Rasi G.e, and Sinibaldi Vallebona P.f
- Published
- 2006
10. Again on the difficulty of seeking ATM localization
- Author
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Oricchio E, Saladino C, Iacovelli S, Soddu S, and Cundari E .
- Published
- 2006
11. HYPOTHESIS: SERUM CHOLESTEROL AND SELF-HARM BEHAVIOR
- Author
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Sarchiapone, Marco, Alec, Roy, Vladimir, Carli, Giovanni, Camardese, and SERGIO DE RISIO, INES ORICCHIO E.
- Subjects
self-harm behavior ,SERUM CHOLESTEROL - Published
- 1998
12. p53 Localization at Centrosomes during Mitosis and Postmitotic Checkpoint Are ATM-dependent and Require Serine 15 Phosphorylation
- Author
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Tritarelli, A., primary, Oricchio, E., additional, Ciciarello, M., additional, Mangiacasale, R., additional, Palena, A., additional, Lavia, P., additional, Soddu, S., additional, and Cundari, E., additional
- Published
- 2004
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13. Pan-SRC kinase inhibition blocks B-cell receptor oncogenic signaling in non-Hodgkin lymphoma
- Author
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Battistello, E, Katanayeva, N, Dheilly, E, Tavernari, D, Donaldson, MC, Bonsignore, L, Thome, M, Christie, AL, Murakami, MA, Michielin, O, Ciriello, G, Zoete, V, and Oricchio, E
14. p53 Localization at Centrosomes during Mitosis and Postmitotic Checkpoint are ATM-Dependent and Require Serine 15 Phosphorylation
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Rosamaria Mangiacasale, Antonella Palena, Patrizia Lavia, Marilena Ciciarello, A. Tritarelli, Silvia Soddu, Enrico Cundari, Elisa Oricchio, Tritarelli, A., Oricchio, E., Ciciarello, M., Mangiacasale, R., Palena, A., Lavia, P., Soddu, S., and Cundari, E
- Subjects
DNA-Binding Protein ,Mitosis ,Cell Cycle Proteins ,Centrosome cycle ,Ataxia Telangiectasia Mutated Proteins ,Spindle Apparatus ,Protein Serine-Threonine Kinases ,Biology ,Protein-Serine-Threonine Kinase ,PLK1 ,Cell Line ,Ataxia Telangiectasia Mutated Protein ,chemistry.chemical_compound ,Genetic ,Tubulin ,Cell Cycle Protein ,Serine ,Humans ,Phosphorylation ,Molecular Biology ,Centrosome ,Tumor Suppressor Protein ,Spindle Apparatu ,Tumor Suppressor Proteins ,Nocodazole ,Articles ,Cell Biology ,Cell cycle ,Mitosi ,Cell biology ,DNA-Binding Proteins ,Spindle checkpoint ,chemistry ,Mutation ,Tumor Suppressor Protein p53 ,Human - Abstract
We recently demonstrated that the p53 oncosuppressor associates to centrosomes in mitosis and this association is disrupted by treatments with microtubule-depolymerizing agents. Here, we show that ATM, an upstream activator of p53 after DNA damage, is essential for p53 centrosomal localization and is required for the activation of the postmitotic checkpoint after spindle disruption. In mitosis, p53 failed to associate with centrosomes in two ATM-deficient, ataxiatelangiectasia–derived cell lines. Wild-type ATM gene transfer reestablished the centrosomal localization of p53 in these cells. Furthermore, wild-type p53 protein, but not the p53-S15A mutant, not phosphorylatable by ATM, localized at centrosomes when expressed in p53-null K562 cells. Finally, Ser15 phosphorylation of endogenous p53 was detected at centrosomes upon treatment with phosphatase inhibitors, suggesting that a p53 dephosphorylation step at centrosome contributes to sustain the cell cycle program in cells with normal mitotic spindles. When dissociated from centrosomes by treatments with spindle inhibitors, p53 remained phosphorylated at Ser15. AT cells, which are unable to phosphorylate p53, did not undergo postmitotic proliferation arrest after nocodazole block and release. These data demonstrate that ATM is required for p53 localization at centrosome and support the existence of a surveillance mechanism for inhibiting DNA reduplication downstream of the spindle assembly checkpoint
- Published
- 2004
15. Engineered allogeneic T cells decoupling T-cell-receptor and CD3 signalling enhance the antitumour activity of bispecific antibodies.
- Author
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Kapetanovic E, Weber CR, Bruand M, Pöschl D, Kucharczyk J, Hirth E, Dietsche C, Khan R, Wagner B, Belli O, Vazquez-Lombardi R, Castellanos-Rueda R, Di Roberto RB, Kalinka K, Raess L, Ly K, Rai S, Dittrich PS, Platt RJ, Oricchio E, and Reddy ST
- Abstract
Bispecific antibodies (biAbs) used in cancer immunotherapies rely on functional autologous T cells, which are often damaged and depleted in patients with haematological malignancies and in other immunocompromised patients. The adoptive transfer of allogeneic T cells from healthy donors can enhance the efficacy of biAbs, but donor T cells binding to host-cell antigens cause an unwanted alloreactive response. Here we show that allogeneic T cells engineered with a T-cell receptor that does not convert antigen binding into cluster of differentiation 3 (CD3) signalling decouples antigen-mediated T-cell activation from T-cell cytotoxicity while preserving the surface expression of the T-cell-receptor-CD3 signalling complex as well as biAb-mediated CD3 signalling and T-cell activation. In mice with CD19
+ tumour xenografts, treatment with the engineered human cells in combination with blinatumomab (a clinically approved biAb) led to the recognition and clearance of tumour cells in the absence of detectable alloreactivity. Our findings support the development of immunotherapies combining biAbs and 'off-the-shelf' allogeneic T cells., (© 2024. The Author(s).)- Published
- 2024
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16. Antibody-peptide conjugates deliver covalent inhibitors blocking oncogenic cathepsins.
- Author
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Petruzzella A, Bruand M, Santamaria-Martínez A, Katanayeva N, Reymond L, Wehrle S, Georgeon S, Inel D, van Dalen FJ, Viertl D, Lau K, Pojer F, Schottelius M, Zoete V, Verdoes M, Arber C, Correia BE, and Oricchio E
- Subjects
- Humans, Animals, Mice, Cell Line, Tumor, Drug Delivery Systems methods, Immunoconjugates pharmacology, Immunoconjugates chemistry, Neoplasms drug therapy, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Cathepsins antagonists & inhibitors, Cathepsins metabolism, Peptides chemistry, Peptides pharmacology
- Abstract
Cysteine cathepsins are a family of proteases that are relevant therapeutic targets for the treatment of different cancers and other diseases. However, no clinically approved drugs for these proteins exist, as their systemic inhibition can induce deleterious side effects. To address this problem, we developed a modular antibody-based platform for targeted drug delivery by conjugating non-natural peptide inhibitors (NNPIs) to antibodies. NNPIs were functionalized with reactive warheads for covalent inhibition, optimized with deep saturation mutagenesis and conjugated to antibodies to enable cell-type-specific delivery. Our antibody-peptide inhibitor conjugates specifically blocked the activity of cathepsins in different cancer cells, as well as osteoclasts, and showed therapeutic efficacy in vitro and in vivo. Overall, our approach allows for the rapid design of selective cathepsin inhibitors and can be generalized to inhibit a broad class of proteases in cancer and other diseases., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2024
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17. Cancer Evolution: A Multifaceted Affair.
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Ciriello G, Magnani L, Aitken SJ, Akkari L, Behjati S, Hanahan D, Landau DA, Lopez-Bigas N, Lupiáñez DG, Marine JC, Martin-Villalba A, Natoli G, Obenauf AC, Oricchio E, Scaffidi P, Sottoriva A, Swarbrick A, Tonon G, Vanharanta S, and Zuber J
- Subjects
- Humans, Epigenomics, Precision Medicine, Tumor Microenvironment genetics, Neoplasms genetics, Neoplasms pathology
- Abstract
Cancer cells adapt and survive through the acquisition and selection of molecular modifications. This process defines cancer evolution. Building on a theoretical framework based on heritable genetic changes has provided insights into the mechanisms supporting cancer evolution. However, cancer hallmarks also emerge via heritable nongenetic mechanisms, including epigenetic and chromatin topological changes, and interactions between tumor cells and the tumor microenvironment. Recent findings on tumor evolutionary mechanisms draw a multifaceted picture where heterogeneous forces interact and influence each other while shaping tumor progression. A comprehensive characterization of the cancer evolutionary toolkit is required to improve personalized medicine and biomarker discovery., Significance: Tumor evolution is fueled by multiple enabling mechanisms. Importantly, genetic instability, epigenetic reprogramming, and interactions with the tumor microenvironment are neither alternative nor independent evolutionary mechanisms. As demonstrated by findings highlighted in this perspective, experimental and theoretical approaches must account for multiple evolutionary mechanisms and their interactions to ultimately understand, predict, and steer tumor evolution., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
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18. Chromatin organization in red triangles.
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Oricchio E
- Subjects
- Chromatin genetics
- Published
- 2023
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19. De novo design of protein interactions with learned surface fingerprints.
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Gainza P, Wehrle S, Van Hall-Beauvais A, Marchand A, Scheck A, Harteveld Z, Buckley S, Ni D, Tan S, Sverrisson F, Goverde C, Turelli P, Raclot C, Teslenko A, Pacesa M, Rosset S, Georgeon S, Marsden J, Petruzzella A, Liu K, Xu Z, Chai Y, Han P, Gao GF, Oricchio E, Fierz B, Trono D, Stahlberg H, Bronstein M, and Correia BE
- Subjects
- Humans, Proteomics, Protein Interaction Maps, Binding Sites, Synthetic Biology, Proteins chemistry, Proteins metabolism, Protein Binding, Deep Learning, Computer Simulation
- Abstract
Physical interactions between proteins are essential for most biological processes governing life
1 . However, the molecular determinants of such interactions have been challenging to understand, even as genomic, proteomic and structural data increase. This knowledge gap has been a major obstacle for the comprehensive understanding of cellular protein-protein interaction networks and for the de novo design of protein binders that are crucial for synthetic biology and translational applications2-9 . Here we use a geometric deep-learning framework operating on protein surfaces that generates fingerprints to describe geometric and chemical features that are critical to drive protein-protein interactions10 . We hypothesized that these fingerprints capture the key aspects of molecular recognition that represent a new paradigm in the computational design of novel protein interactions. As a proof of principle, we computationally designed several de novo protein binders to engage four protein targets: SARS-CoV-2 spike, PD-1, PD-L1 and CTLA-4. Several designs were experimentally optimized, whereas others were generated purely in silico, reaching nanomolar affinity with structural and mutational characterization showing highly accurate predictions. Overall, our surface-centric approach captures the physical and chemical determinants of molecular recognition, enabling an approach for the de novo design of protein interactions and, more broadly, of artificial proteins with function., (© 2023. The Author(s).)- Published
- 2023
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20. Whole-genome doubling drives oncogenic loss of chromatin segregation.
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Lambuta RA, Nanni L, Liu Y, Diaz-Miyar J, Iyer A, Tavernari D, Katanayeva N, Ciriello G, and Oricchio E
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- Humans, Carcinogenesis genetics, Epigenesis, Genetic, Disease Progression, Transcription, Genetic, Gene Expression Regulation, Neoplastic, Chromatin genetics, Chromatin metabolism, Chromosome Aberrations, Neoplasms genetics, Chromosomes, Human genetics, Genome, Human genetics, Chromosome Segregation genetics
- Abstract
Whole-genome doubling (WGD) is a recurrent event in human cancers and it promotes chromosomal instability and acquisition of aneuploidies
1-8 . However, the three-dimensional organization of chromatin in WGD cells and its contribution to oncogenic phenotypes are currently unknown. Here we show that in p53-deficient cells, WGD induces loss of chromatin segregation (LCS). This event is characterized by reduced segregation between short and long chromosomes, A and B subcompartments and adjacent chromatin domains. LCS is driven by the downregulation of CTCF and H3K9me3 in cells that bypassed activation of the tetraploid checkpoint. Longitudinal analyses revealed that LCS primes genomic regions for subcompartment repositioning in WGD cells. This results in chromatin and epigenetic changes associated with oncogene activation in tumours ensuing from WGD cells. Notably, subcompartment repositioning events were largely independent of chromosomal alterations, which indicates that these were complementary mechanisms contributing to tumour development and progression. Overall, LCS initiates chromatin conformation changes that ultimately result in oncogenic epigenetic and transcriptional modifications, which suggests that chromatin evolution is a hallmark of WGD-driven cancer., (© 2023. The Author(s).)- Published
- 2023
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21. Epigenetic balance in DLBCL.
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Oricchio E
- Subjects
- Epigenesis, Genetic, Epigenomics, Humans, Lymphoma, Large B-Cell, Diffuse genetics
- Published
- 2021
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22. Nongenetic Evolution Drives Lung Adenocarcinoma Spatial Heterogeneity and Progression.
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Tavernari D, Battistello E, Dheilly E, Petruzzella AS, Mina M, Sordet-Dessimoz J, Peters S, Krueger T, Gfeller D, Riggi N, Oricchio E, Letovanec I, and Ciriello G
- Subjects
- Disease Progression, Genetic Heterogeneity, Humans, Tumor Microenvironment, Adenocarcinoma of Lung genetics, Lung Neoplasms genetics
- Abstract
Cancer evolution determines molecular and morphologic intratumor heterogeneity and challenges the design of effective treatments. In lung adenocarcinoma, disease progression and prognosis are associated with the appearance of morphologically diverse tumor regions, termed histologic patterns. However, the link between molecular and histologic features remains elusive. Here, we generated multiomics and spatially resolved molecular profiles of histologic patterns from primary lung adenocarcinoma, which we integrated with molecular data from >2,000 patients. The transition from indolent to aggressive patterns was not driven by genetic alterations but by epigenetic and transcriptional reprogramming reshaping cancer cell identity. A signature quantifying this transition was an independent predictor of patient prognosis in multiple human cohorts. Within individual tumors, highly multiplexed protein spatial profiling revealed coexistence of immune desert, inflamed, and excluded regions, which matched histologic pattern composition. Our results provide a detailed molecular map of lung adenocarcinoma intratumor spatial heterogeneity, tracing nongenetic routes of cancer evolution. SIGNIFICANCE: Lung adenocarcinomas are classified based on histologic pattern prevalence. However, individual tumors exhibit multiple patterns with unknown molecular features. We characterized nongenetic mechanisms underlying intratumor patterns and molecular markers predicting patient prognosis. Intratumor patterns determined diverse immune microenvironments, warranting their study in the context of current immunotherapies. This article is highlighted in the In This Issue feature, p. 1307 ., (©2021 American Association for Cancer Research.)
- Published
- 2021
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23. Systematic inference and comparison of multi-scale chromatin sub-compartments connects spatial organization to cell phenotypes.
- Author
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Liu Y, Nanni L, Sungalee S, Zufferey M, Tavernari D, Mina M, Ceri S, Oricchio E, and Ciriello G
- Abstract
Chromatin compartmentalization reflects biological activity. However, inference of chromatin sub-compartments and compartment domains from chromosome conformation capture (Hi-C) experiments is limited by data resolution. As a result, these have been characterized only in a few cell types and systematic comparisons across multiple tissues and conditions are missing. Here, we present Calder, an algorithmic approach that enables the identification of multi-scale sub-compartments at variable data resolution. Calder allows to infer and compare chromatin sub-compartments and compartment domains in >100 cell lines. Our results reveal sub-compartments enriched for poised chromatin states and undergoing spatial repositioning during lineage differentiation and oncogenic transformation.
- Published
- 2021
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24. Histone acetylation dynamics modulates chromatin conformation and allele-specific interactions at oncogenic loci.
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Sungalee S, Liu Y, Lambuta RA, Katanayeva N, Donaldson Collier M, Tavernari D, Roulland S, Ciriello G, and Oricchio E
- Subjects
- Acetylation, Base Pairing genetics, Cell Line, Tumor, Enhancer Elements, Genetic, Epigenesis, Genetic, Gene Dosage, Humans, Lysine metabolism, Promoter Regions, Genetic, Alleles, Chromatin chemistry, Genetic Loci, Histones metabolism, Nucleic Acid Conformation, Oncogenes
- Abstract
In cancer cells, enhancer hijacking mediated by chromosomal alterations and/or increased deposition of acetylated histone H3 lysine 27 (H3K27ac) can support oncogene expression. However, how the chromatin conformation of enhancer-promoter interactions is affected by these events is unclear. In the present study, by comparing chromatin structure and H3K27ac levels in normal and lymphoma B cells, we show that enhancer-promoter-interacting regions assume different conformations according to the local abundance of H3K27ac. Genetic or pharmacological depletion of H3K27ac decreases the frequency and the spreading of these interactions, altering oncogene expression. Moreover, enhancer hijacking mediated by chromosomal translocations influences the epigenetic status of the regions flanking the breakpoint, prompting the formation of distinct intrachromosomal interactions in the two homologous chromosomes. These interactions are accompanied by allele-specific gene expression changes. Overall, our work indicates that H3K27ac dynamics modulates interaction frequency between regulatory regions and can lead to allele-specific chromatin configurations to sustain oncogene expression.
- Published
- 2021
- Full Text
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25. De novo protein design enables the precise induction of RSV-neutralizing antibodies.
- Author
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Sesterhenn F, Yang C, Bonet J, Cramer JT, Wen X, Wang Y, Chiang CI, Abriata LA, Kucharska I, Castoro G, Vollers SS, Galloux M, Dheilly E, Rosset S, Corthésy P, Georgeon S, Villard M, Richard CA, Descamps D, Delgado T, Oricchio E, Rameix-Welti MA, Más V, Ervin S, Eléouët JF, Riffault S, Bates JT, Julien JP, Li Y, Jardetzky T, Krey T, and Correia BE
- Subjects
- Amino Acid Motifs, Humans, Immunodominant Epitopes immunology, Protein Conformation, Recombinant Fusion Proteins immunology, Respiratory Syncytial Virus Vaccines immunology, Single-Domain Antibodies chemistry, Single-Domain Antibodies immunology, Antibodies, Neutralizing biosynthesis, Computational Biology methods, Immunodominant Epitopes chemistry, Protein Engineering methods, Recombinant Fusion Proteins chemistry, Respiratory Syncytial Virus Vaccines chemistry, Respiratory Syncytial Virus, Human immunology
- Abstract
De novo protein design has been successful in expanding the natural protein repertoire. However, most de novo proteins lack biological function, presenting a major methodological challenge. In vaccinology, the induction of precise antibody responses remains a cornerstone for next-generation vaccines. Here, we present a protein design algorithm called TopoBuilder, with which we engineered epitope-focused immunogens displaying complex structural motifs. In both mice and nonhuman primates, cocktails of three de novo-designed immunogens induced robust neutralizing responses against the respiratory syncytial virus. Furthermore, the immunogens refocused preexisting antibody responses toward defined neutralization epitopes. Overall, our design approach opens the possibility of targeting specific epitopes for the development of vaccines and therapeutic antibodies and, more generally, will be applicable to the design of de novo proteins displaying complex functional motifs., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2020
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26. Cathepsin S Regulates Antigen Processing and T Cell Activity in Non-Hodgkin Lymphoma.
- Author
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Dheilly E, Battistello E, Katanayeva N, Sungalee S, Michaux J, Duns G, Wehrle S, Sordet-Dessimoz J, Mina M, Racle J, Farinha P, Coukos G, Gfeller D, Mottok A, Kridel R, Correia BE, Steidl C, Bassani-Sternberg M, Ciriello G, Zoete V, and Oricchio E
- Subjects
- Animals, Apoptosis, B-Lymphocytes immunology, Cell Proliferation, Female, Germinal Center immunology, Humans, Lymphocyte Activation immunology, Lymphoma, Non-Hodgkin genetics, Lymphoma, Non-Hodgkin pathology, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, T-Lymphocytes, Helper-Inducer immunology, Tumor Cells, Cultured, Antigen Presentation immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Cathepsins genetics, Lymphoma, Non-Hodgkin immunology, Mutation, Tumor Microenvironment immunology
- Abstract
Genomic alterations in cancer cells can influence the immune system to favor tumor growth. In non-Hodgkin lymphoma, physiological interactions between B cells and the germinal center microenvironment are coopted to sustain cancer cell proliferation. We found that follicular lymphoma patients harbor a recurrent hotspot mutation targeting tyrosine 132 (Y132D) in cathepsin S (CTSS) that enhances protein activity. CTSS regulates antigen processing and CD4
+ and CD8+ T cell-mediated immune responses. Loss of CTSS activity reduces lymphoma growth by limiting communication with CD4+ T follicular helper cells while inducing antigen diversification and activation of CD8+ T cells. Overall, our results suggest that CTSS inhibition has non-redundant therapeutic potential to enhance anti-tumor immune responses in indolent and aggressive lymphomas., Competing Interests: Declaration of Interests The authors declare no competing financial interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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27. EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains.
- Author
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Donaldson-Collier MC, Sungalee S, Zufferey M, Tavernari D, Katanayeva N, Battistello E, Mina M, Douglass KM, Rey T, Raynaud F, Manley S, Ciriello G, and Oricchio E
- Subjects
- Animals, Cell Line, Tumor, DNA Methylation genetics, Epigenomics methods, Gene Expression Regulation, Neoplastic genetics, Gene Silencing physiology, Histones genetics, Humans, Mice, Promoter Regions, Genetic genetics, Chromatin genetics, Enhancer of Zeste Homolog 2 Protein genetics, Epigenesis, Genetic genetics, Mutation genetics, Transcription, Genetic genetics
- Abstract
Chromatin is organized into topologically associating domains (TADs) enriched in distinct histone marks. In cancer, gain-of-function mutations in the gene encoding the enhancer of zeste homolog 2 protein (EZH2) lead to a genome-wide increase in histone-3 Lys27 trimethylation (H3K27me3) associated with transcriptional repression. However, the effects of these epigenetic changes on the structure and function of chromatin domains have not been explored. Here, we found a functional interplay between TADs and epigenetic and transcriptional changes mediated by mutated EZH2. Altered EZH2 (p.Tyr646* (EZH2
Y646X )) led to silencing of entire domains, synergistically inactivating multiple tumor suppressors. Intra-TAD gene silencing was coupled with changes of interactions between gene promoter regions. Notably, gene expression and chromatin interactions were restored by pharmacological inhibition of EZH2Y646X . Our results indicate that EZH2Y646X alters the topology and function of chromatin domains to promote synergistic oncogenic programs.- Published
- 2019
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28. Comparison of computational methods for the identification of topologically associating domains.
- Author
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Zufferey M, Tavernari D, Oricchio E, and Ciriello G
- Subjects
- Animals, Chromosomes, Humans, Mice, Chromatin Assembly and Disassembly, Genomics methods
- Abstract
Background: Chromatin folding gives rise to structural elements among which are clusters of densely interacting DNA regions termed topologically associating domains (TADs). TADs have been characterized across multiple species, tissue types, and differentiation stages, sometimes in association with regulation of biological functions. The reliability and reproducibility of these findings are intrinsically related with the correct identification of these domains from high-throughput chromatin conformation capture (Hi-C) experiments., Results: Here, we test and compare 22 computational methods to identify TADs across 20 different conditions. We find that TAD sizes and numbers vary significantly among callers and data resolutions, challenging the definition of an average TAD size, but strengthening the hypothesis that TADs are hierarchically organized domains, rather than disjoint structural elements. Performances of these methods differ based on data resolution and normalization strategy, but a core set of TAD callers consistently retrieve reproducible domains, even at low sequencing depths, that are enriched for TAD-associated biological features., Conclusions: This study provides a reference for the analysis of chromatin domains from Hi-C experiments and useful guidelines for choosing a suitable approach based on the experimental design, available data, and biological question of interest.
- Published
- 2018
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29. Pan-SRC kinase inhibition blocks B-cell receptor oncogenic signaling in non-Hodgkin lymphoma.
- Author
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Battistello E, Katanayeva N, Dheilly E, Tavernari D, Donaldson MC, Bonsignore L, Thome M, Christie AL, Murakami MA, Michielin O, Ciriello G, Zoete V, and Oricchio E
- Subjects
- Adenine analogs & derivatives, Animals, Cell Line, Tumor, Cell Transformation, Neoplastic metabolism, Disease Models, Animal, Drug Resistance, Neoplasm genetics, Gene Expression, Genes, myc, Humans, Lymphoma, Non-Hodgkin drug therapy, Lymphoma, Non-Hodgkin pathology, Mice, Mice, Knockout, Piperidines, Pyrazoles pharmacology, Pyrimidines pharmacology, Xenograft Model Antitumor Assays, Lymphoma, Non-Hodgkin etiology, Lymphoma, Non-Hodgkin metabolism, Protein Kinase Inhibitors pharmacology, Receptors, Antigen, B-Cell metabolism, Signal Transduction drug effects, src-Family Kinases antagonists & inhibitors
- Abstract
In diffuse large B-cell lymphoma (DLBCL), activation of the B-cell receptor (BCR) promotes multiple oncogenic signals, which are essential for tumor proliferation. Inhibition of the Bruton's tyrosine kinase (BTK), a BCR downstream target, is therapeutically effective only in a subgroup of patients with DLBCL. Here, we used lymphoma cells isolated from patients with DLBCL to measure the effects of targeted therapies on BCR signaling and to anticipate response. In lymphomas resistant to BTK inhibition, we show that blocking BTK activity enhanced tumor dependencies from alternative oncogenic signals downstream of the BCR, converging on MYC upregulation. To completely ablate the activity of the BCR, we genetically and pharmacologically repressed the activity of the SRC kinases LYN, FYN, and BLK, which are responsible for the propagation of the BCR signal. Inhibition of these kinases strongly reduced tumor growth in xenografts and cell lines derived from patients with DLBCL independent of their molecular subtype, advancing the possibility to be relevant therapeutic targets in broad and diverse groups of DLBCL patients., (© 2018 by The American Society of Hematology.)
- Published
- 2018
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30. Sestrin1, a tumor suppressor that can be rescued.
- Author
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Donaldson MC, Katanayeva N, and Oricchio E
- Abstract
SESTRIN1 is a tumor suppressor in follicular lymphoma that controls mTORC1 activity and it is inactivated by chromosomal deletions or epigenetically silenced by mutant EZH2
Y641X . Pharmacological inhibition of EZH2 promotes SESTRIN1 re-expression and it restores its tumor suppressive activity, suggesting the possibility to epigenetically control mTORC1 activity.- Published
- 2017
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31. Conditional Selection of Genomic Alterations Dictates Cancer Evolution and Oncogenic Dependencies.
- Author
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Mina M, Raynaud F, Tavernari D, Battistello E, Sungalee S, Saghafinia S, Laessle T, Sanchez-Vega F, Schultz N, Oricchio E, and Ciriello G
- Subjects
- Gene Expression Profiling, Genomics, Humans, Models, Genetic, Algorithms, Carcinogenesis, Evolution, Molecular, Neoplasms genetics, Selection, Genetic
- Abstract
Cancer evolves through the emergence and selection of molecular alterations. Cancer genome profiling has revealed that specific events are more or less likely to be co-selected, suggesting that the selection of one event depends on the others. However, the nature of these evolutionary dependencies and their impact remain unclear. Here, we designed SELECT, an algorithmic approach to systematically identify evolutionary dependencies from alteration patterns. By analyzing 6,456 genomes from multiple tumor types, we constructed a map of oncogenic dependencies associated with cellular pathways, transcriptional readouts, and therapeutic response. Finally, modeling of cancer evolution shows that alteration dependencies emerge only under conditional selection. These results provide a framework for the design of strategies to predict cancer progression and therapeutic response., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
32. Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma.
- Author
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Oricchio E, Katanayeva N, Donaldson MC, Sungalee S, Pasion JP, Béguelin W, Battistello E, Sanghvi VR, Jiang M, Jiang Y, Teater M, Parmigiani A, Budanov AV, Chan FC, Shah SP, Kridel R, Melnick AM, Ciriello G, and Wendel HG
- Subjects
- Animals, Chromosome Deletion, Chromosomes, Human, Pair 6 genetics, Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors, Gene Silencing, Genetic Testing, Genome, Human, Heat-Shock Proteins deficiency, Humans, Mice, Mutation genetics, Protein Biosynthesis, RNA, Messenger genetics, RNA, Messenger metabolism, Enhancer of Zeste Homolog 2 Protein metabolism, Epigenesis, Genetic, Heat-Shock Proteins genetics, Lymphoma, Follicular genetics, Mechanistic Target of Rapamycin Complex 1 metabolism
- Abstract
Follicular lymphoma (FL) is an incurable form of B cell lymphoma. Genomic studies have cataloged common genetic lesions in FL such as translocation t(14;18), frequent losses of chromosome 6q, and mutations in epigenetic regulators such as EZH2 Using a focused genetic screen, we identified SESTRIN1 as a relevant target of the 6q deletion and demonstrate tumor suppression by SESTRIN1 in vivo. Moreover, SESTRIN1 is a direct target of the lymphoma-specific EZH2 gain-of-function mutation ( EZH2
Y641X ). SESTRIN1 inactivation disrupts p53-mediated control of mammalian target of rapamycin complex 1 (mTORC1) and enables mRNA translation under genotoxic stress. SESTRIN1 loss represents an alternative to RRAGC mutations that maintain mTORC1 activity under nutrient starvation. The antitumor efficacy of pharmacological EZH2 inhibition depends on SESTRIN1, indicating that mTORC1 control is a critical function of EZH2 in lymphoma. Conversely, EZH2Y641X mutant lymphomas show increased sensitivity to RapaLink-1, a bifunctional mTOR inhibitor. Hence, SESTRIN1 contributes to the genetic and epigenetic control of mTORC1 in lymphoma and influences responses to targeted therapies., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2017
- Full Text
- View/download PDF
33. Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells.
- Author
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Boice M, Salloum D, Mourcin F, Sanghvi V, Amin R, Oricchio E, Jiang M, Mottok A, Denis-Lagache N, Ciriello G, Tam W, Teruya-Feldstein J, de Stanchina E, Chan WC, Malek SN, Ennishi D, Brentjens RJ, Gascoyne RD, Cogné M, Tarte K, and Wendel HG
- Subjects
- Animals, Antigens, CD19 immunology, B-Lymphocytes immunology, Cell Proliferation, Humans, Lymphocyte Activation, Lymphoma, Follicular genetics, Mice, Neoplasms, Experimental genetics, Neoplasms, Experimental therapy, Protein Domains, Protein Engineering, Receptors, Tumor Necrosis Factor, Member 14 chemistry, Receptors, Tumor Necrosis Factor, Member 14 metabolism, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Tumor Microenvironment, Tumor Suppressor Proteins chemistry, Tumor Suppressor Proteins metabolism, Xenograft Model Antitumor Assays, Adoptive Transfer methods, Lymphoma, Follicular therapy, Receptors, Immunologic metabolism, Receptors, Tumor Necrosis Factor, Member 14 genetics, T-Lymphocytes immunology, Tumor Suppressor Proteins genetics
- Abstract
The HVEM (TNFRSF14) receptor gene is among the most frequently mutated genes in germinal center lymphomas. We report that loss of HVEM leads to cell-autonomous activation of B cell proliferation and drives the development of GC lymphomas in vivo. HVEM-deficient lymphoma B cells also induce a tumor-supportive microenvironment marked by exacerbated lymphoid stroma activation and increased recruitment of T follicular helper (T
FH ) cells. These changes result from the disruption of inhibitory cell-cell interactions between the HVEM and BTLA (B and T lymphocyte attenuator) receptors. Accordingly, administration of the HVEM ectodomain protein (solHVEM(P37-V202) ) binds BTLA and restores tumor suppression. To deliver solHVEM to lymphomas in vivo, we engineered CD19-targeted chimeric antigen receptor (CAR) T cells that produce solHVEM locally and continuously. These modified CAR-T cells show enhanced therapeutic activity against xenografted lymphomas. Hence, the HVEM-BTLA axis opposes lymphoma development, and our study illustrates the use of CAR-T cells as "micro-pharmacies" able to deliver an anti-cancer protein., (Copyright © 2016 Elsevier Inc. All rights reserved.)- Published
- 2016
- Full Text
- View/download PDF
34. Generation and characterization of a single-chain anti-EphA2 antibody.
- Author
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Goldgur Y, Susi P, Karelehto E, Sanmark H, Lamminmäki U, Oricchio E, Wendel HG, Nikolov DB, and Himanen JP
- Subjects
- Amino Acid Sequence, Animals, Antibody Affinity, Binding Sites, Antibody, COS Cells, Cell Line, Tumor, Chlorocebus aethiops, HEK293 Cells, Humans, Molecular Sequence Data, Single-Chain Antibodies chemistry, Receptor, EphA2 immunology, Single-Chain Antibodies immunology
- Abstract
Recombinant antibody phage library technology provides multiple advantages, including that human antibodies can be generated against proteins that are highly conserved between species. We used this technology to isolate and characterize an anti-EphA2 single-chain antibody. We show that the antibody binds the antigen with 1:1 stoichiometry and has high specificity for EphA2. The crystal structure of the complex reveals that the antibody targets the same receptor surface cavity as the ephrin ligand. Specifically, a lengthy CDR-H3 loop protrudes deep into the ligand-binding cavity, with several hydrophobic residues at its tip forming an anchor-like structure buried within the hydrophobic Eph pocket, in a way similar to the ephrin receptor-binding loop in the Eph/ephrin structures. Consequently, the antibody blocks ephrin binding to EphA2. Furthermore, it induces apoptosis and reduces cell proliferation in lymphoma cells lines. Since Ephs are important mediators of tumorigenesis, such antibodies could have applications both in research and therapy.
- Published
- 2014
- Full Text
- View/download PDF
35. Genomic studies indicate a novel combination therapy for follicular lymphoma.
- Author
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Oricchio E and Wendel HG
- Abstract
Follicular lymphoma (FL) is an incurable form of B-cell lymphoma. Genomic alterations that inactivate RB signaling are surprisingly common in indolent FL. We show that FLs that are positive for phosphorylated RB respond to dual CDK4/BCL2 inhibition. Our results imply that RB phosphorylation identifies patients likely to benefit from such dual intervention., (© 2016 Taylor & Francis Group, LLC.)
- Published
- 2014
- Full Text
- View/download PDF
36. A cell engineering strategy to enhance the safety of stem cell therapies.
- Author
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Oricchio E, Papapetrou EP, Lafaille F, Ganat YM, Kriks S, Ortega-Molina A, Mark WH, Teruya-Feldstein J, Huse JT, Reuter V, Sadelain M, Studer L, and Wendel HG
- Subjects
- Animals, Carrier Proteins metabolism, Cell Line, Dopaminergic Neurons cytology, Dopaminergic Neurons diagnostic imaging, Female, Humans, Induced Pluripotent Stem Cells transplantation, Magnetic Resonance Imaging, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, SCID, Neoplasms therapy, Neurogenesis, Proto-Oncogene Proteins c-myc antagonists & inhibitors, Proto-Oncogene Proteins c-myc metabolism, Radiography, Thyroid Hormones metabolism, Thyroid Hormone-Binding Proteins, Cell Engineering, Cell- and Tissue-Based Therapy standards, Induced Pluripotent Stem Cells cytology
- Abstract
The long-term risk of malignancy associated with stem cell therapies is a significant concern in the clinical application of this exciting technology. We report a cancer-selective strategy to enhance the safety of stem cell therapies. Briefly, using a cell engineering approach, we show that aggressive cancers derived from human or murine induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) are strikingly sensitive to temporary MYC blockade. On the other hand, differentiated tissues derived from human or mouse iPSCs can readily tolerate temporary MYC inactivation. In cancer cells, endogenous MYC is required to maintain the metabolic and epigenetic functions of the embryonic and cancer-specific pyruvate kinase M2 isoform (PKM2). In summary, our results implicate PKM2 in cancer's increased MYC dependence and indicate dominant MYC inhibition as a cancer-selective fail-safe for stem cell therapies., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
37. Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy.
- Author
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Oricchio E, Ciriello G, Jiang M, Boice MH, Schatz JH, Heguy A, Viale A, de Stanchina E, Teruya-Feldstein J, Bouska A, McKeithan T, Sander C, Tam W, Seshan VE, Chan WC, Chaganti RS, and Wendel HG
- Subjects
- Animals, Cell Line, Tumor, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 4 genetics, Cyclin-Dependent Kinase 4 metabolism, Cyclin-Dependent Kinase Inhibitor p15 genetics, Cyclin-Dependent Kinase Inhibitor p15 metabolism, Cyclin-Dependent Kinase Inhibitor p16 genetics, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Humans, Male, Mice, Neoplasms, Experimental drug therapy, Neoplasms, Experimental genetics, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Lymphoma, Follicular drug therapy, Lymphoma, Follicular genetics, Lymphoma, Follicular metabolism, Lymphoma, Follicular pathology, Retinoblastoma Protein genetics, Retinoblastoma Protein metabolism
- Abstract
Loss of cell cycle controls is a hallmark of cancer and has a well-established role in aggressive B cell malignancies. However, the role of such lesions in indolent follicular lymphoma (FL) is unclear and individual lesions have been observed with low frequency. By analyzing genomic data from two large cohorts of indolent FLs, we identify a pattern of mutually exclusive (P = 0.003) genomic lesions that impair the retinoblastoma (RB) pathway in nearly 50% of FLs. These alterations include homozygous and heterozygous deletions of the p16/CDKN2a/b (7%) and RB1 (12%) loci, and more frequent gains of chromosome 12 that include CDK4 (29%). These aberrations are associated with high-risk disease by the FL prognostic index (FLIPI), and studies in a murine FL model confirm their pathogenic role in indolent FL. Increased CDK4 kinase activity toward RB1 is readily measured in tumor samples and indicates an opportunity for CDK4 inhibition. We find that dual CDK4 and BCL2 inhibitor treatment is safe and effective against available models of FL. In summary, frequent RB pathway lesions in indolent, high-risk FLs indicate an untapped therapeutic opportunity., (© 2014 Oricchio et al.)
- Published
- 2014
- Full Text
- View/download PDF
38. Progress against follicular lymphoma.
- Author
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Schatz JH, Oricchio E, Puvvada SD, and Wendel HG
- Subjects
- Animals, Disease Models, Animal, Humans, Mice, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Antineoplastic Agents therapeutic use, Lymphoma, Follicular drug therapy, Protein Kinase Inhibitors therapeutic use
- Abstract
Purpose of Review: To share the recent progress in research and new therapies against follicular lymphoma and highlight the exciting opportunities to improve the treatment of follicular lymphoma., Recent Findings: Follicular lymphoma has been somewhat neglected by the research community, but recent genomic studies have identified key genetic lesions in follicular lymphoma. In addition, a new murine model is available to explore the function of these lesions in the development, progression, and treatment of follicular lymphoma. Moreover, new small-molecule inhibitors are now available that target key pathways in follicular lymphoma including B-cell receptor signaling and histone modifiers., Summary: Follicular lymphoma is a very common and still incurable form of lymphoma. However, recent genomic and in-vivo biological studies are beginning to unveil the molecular drivers of follicular lymphoma. This coincides with the development of effective small-molecule inhibitors against key targets. Together these developments suggest that we are at a long overdue watershed moment in the treatment of follicular lymphoma.
- Published
- 2013
- Full Text
- View/download PDF
39. Functional genomics lead to new therapies in follicular lymphoma.
- Author
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Oricchio E and Wendel HG
- Subjects
- Animals, Antibodies, Monoclonal administration & dosage, Antineoplastic Agents administration & dosage, Antineoplastic Agents metabolism, Antineoplastic Agents therapeutic use, Chromosomes, Human, Pair 6, Genomics methods, Humans, Lymph Nodes metabolism, Lymphoma, Follicular genetics, Lymphoma, Follicular metabolism, Mutation, Neoplasm Proteins administration & dosage, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Neoplasms drug therapy, Neoplasms genetics, Neoplasms metabolism, Protein Isoforms administration & dosage, Protein Isoforms genetics, Protein Isoforms metabolism, Protein Isoforms therapeutic use, Receptor, EphA7 administration & dosage, Receptor, EphA7 genetics, Receptor, EphA7 metabolism, Chromosome Deletion, Drug Delivery Systems, Lymph Nodes drug effects, Lymphoma, Follicular drug therapy, Neoplasm Proteins therapeutic use, Receptor, EphA7 therapeutic use
- Abstract
Recent technological advances allow analysis of genomic changes in cancer in unprecedented detail. The next challenge is to prioritize the multitude of genetic aberrations found and identify therapeutic opportunities. We recently completed a study that illustrates the use of unbiased genetic screens and murine cancer models to find therapeutic targets among complex genomic data. We genetically dissected the common deletion of chromosome 6q and identified the ephrin receptor A7 (EPHA7) as a tumor suppressor in lymphoma. Notably, EPHA7 encodes a soluble splice variant that acts as an extrinsic tumor suppressor. Accordingly, we developed an antibody-based strategy to specifically deliver EPHA7 back to tumors that have lost this gene. Recent sequencing studies have implicated EPHA7 in lung cancer and other tumors, suggesting a broader therapeutic potential for antibody-mediated delivery of this tumor suppressor for cancer therapy. Together, our comprehensive approach provides new insights into cancer biology and may directly lead to the development of new cancer therapies., (© 2013 New York Academy of Sciences.)
- Published
- 2013
- Full Text
- View/download PDF
40. Mining the cancer genome uncovers therapeutic activity of EphA7 against lymphoma.
- Author
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Oricchio E and Wendel HG
- Subjects
- Animals, Antibodies, Monoclonal, Murine-Derived metabolism, Antibodies, Monoclonal, Murine-Derived therapeutic use, Antigens, CD20 metabolism, Antineoplastic Agents metabolism, Antineoplastic Agents therapeutic use, Databases, Genetic, Drug Delivery Systems methods, Genetic Testing, Humans, Lymphoma, B-Cell genetics, MAP Kinase Signaling System, Mice, Protein Isoforms genetics, Protein Isoforms metabolism, RNA Interference, Receptor, EphA7 genetics, Receptor, EphA7 therapeutic use, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins therapeutic use, Rituximab, Solubility, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Data Mining, Genome, Human, Lymphoma, B-Cell therapy, Receptor, EphA7 metabolism, Recombinant Fusion Proteins metabolism
- Abstract
The functional annotation of the cancer genome can reveal new opportunities for cancer therapies. The wealth of genomic data on various cancers has not yet been mined for clinically and therapeutically useful information. We use cross-comparisons of genomic data with the results of unbiased genetic screens to prioritize genomic changes for further study. In this manner, we have identified a soluble variant of the ephrin receptor A7 (EPHA7 (TR) ) as a tumor suppressor that is lost in lymphoma. We also developed antibody-based delivery to restore this tumor suppressor to the cancer cells in situ. We will discuss our strategy of screening genomic data, specific findings concerning EPHA7 and the potential for future discoveries.
- Published
- 2012
- Full Text
- View/download PDF
41. The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma.
- Author
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Oricchio E, Nanjangud G, Wolfe AL, Schatz JH, Mavrakis KJ, Jiang M, Liu X, Bruno J, Heguy A, Olshen AB, Socci ND, Teruya-Feldstein J, Weis-Garcia F, Tam W, Shaknovich R, Melnick A, Himanen JP, Chaganti RS, and Wendel HG
- Subjects
- Animals, Antibodies, Monoclonal, Murine-Derived therapeutic use, Cell Line, Tumor, Chromosomes, Human, Pair 6, Genomics, Humans, Lymphoma, Follicular drug therapy, Lymphoma, Follicular genetics, Male, Mice, Neoplasm Transplantation, RNA Interference, Rituximab, Transplantation, Heterologous, Genes, Tumor Suppressor, Lymphoma, Follicular metabolism, Receptor, EphA7 metabolism
- Abstract
Insights into cancer genetics can lead to therapeutic opportunities. By cross-referencing chromosomal changes with an unbiased genetic screen we identify the ephrin receptor A7 (EPHA7) as a tumor suppressor in follicular lymphoma (FL). EPHA7 is a target of 6q deletions and inactivated in 72% of FLs. Knockdown of EPHA7 drives lymphoma development in a murine FL model. In analogy to its physiological function in brain development, a soluble splice variant of EPHA7 (EPHA7(TR)) interferes with another Eph-receptor and blocks oncogenic signals in lymphoma cells. Consistent with this drug-like activity, administration of the purified EPHA7(TR) protein produces antitumor effects against xenografted human lymphomas. Further, by fusing EPHA7(TR) to the anti-CD20 antibody (rituximab) we can directly target this tumor suppressor to lymphomas in vivo. Our study attests to the power of combining descriptive tumor genomics with functional screens and reveals EPHA7(TR) as tumor suppressor with immediate therapeutic potential., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
42. Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma.
- Author
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Schatz JH, Oricchio E, Wolfe AL, Jiang M, Linkov I, Maragulia J, Shi W, Zhang Z, Rajasekhar VK, Pagano NC, Porco JA Jr, Teruya-Feldstein J, Rosen N, Zelenetz AD, Pelletier J, and Wendel HG
- Subjects
- Animals, Antibiotics, Antineoplastic pharmacology, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Gene Expression Regulation, Enzymologic drug effects, Gene Expression Regulation, Enzymologic genetics, Gene Expression Regulation, Neoplastic drug effects, Gene Expression Regulation, Neoplastic genetics, Humans, Lymphoma drug therapy, Lymphoma genetics, Mechanistic Target of Rapamycin Complex 1, Mice, Multiprotein Complexes, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases genetics, Proteins genetics, Proteins metabolism, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors, Proto-Oncogene Proteins c-pim-1 genetics, RNA Caps genetics, Sirolimus pharmacology, TOR Serine-Threonine Kinases, Transcription Factors genetics, Transcription Factors metabolism, Tumor Cells, Cultured, Lymphoma metabolism, Protein Biosynthesis, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-pim-1 metabolism, RNA Caps metabolism, Signal Transduction
- Abstract
New anticancer drugs that target oncogenic signaling molecules have greatly improved the treatment of certain cancers. However, resistance to targeted therapeutics is a major clinical problem and the redundancy of oncogenic signaling pathways provides back-up mechanisms that allow cancer cells to escape. For example, the AKT and PIM kinases produce parallel oncogenic signals and share many molecular targets, including activators of cap-dependent translation. Here, we show that PIM kinase expression can affect the clinical outcome of lymphoma chemotherapy. We observe the same in animal lymphoma models. Whereas chemoresistance caused by AKT is readily reversed with rapamycin, PIM-mediated resistance is refractory to mTORC1 inhibition. However, both PIM- and AKT-expressing lymphomas depend on cap-dependent translation, and genetic or pharmacological blockade of the translation initiation complex is highly effective against these tumors. The therapeutic effect of blocking cap-dependent translation is mediated, at least in part, by decreased production of short-lived oncoproteins including c-MYC, Cyclin D1, MCL1, and the PIM1/2 kinases themselves. Hence, targeting the convergence of oncogenic survival signals on translation initiation is an effective alternative to combinations of kinase inhibitors., (© 2011 Schatz et al.)
- Published
- 2011
- Full Text
- View/download PDF
43. Mouse models of cancer as biological filters for complex genomic data.
- Author
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Oricchio E, Wolfe AL, Schatz JH, Mavrakis KJ, and Wendel HG
- Subjects
- Animals, Humans, Mice, Databases, Genetic, Disease Models, Animal, Genome genetics, Hematologic Neoplasms genetics, Translational Research, Biomedical
- Abstract
Genetically and pathologically accurate mouse models of leukemia and lymphoma have been developed in recent years. Adoptive transfer of genetically modified hematopoietic progenitor cells enables rapid and highly controlled gain- and loss-of-function studies for these types of cancer. In this Commentary, we discuss how these highly versatile experimental approaches can be used as biological filters to pinpoint transformation-relevant activities from complex cancer genome data. We anticipate that the functional identification of genetic 'drivers' using mouse models of leukemia and lymphoma will facilitate the development of molecular diagnostics and mechanism-based therapies for patients that suffer from these diseases.
- Published
- 2010
- Full Text
- View/download PDF
44. Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia.
- Author
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Mavrakis KJ, Wolfe AL, Oricchio E, Palomero T, de Keersmaecker K, McJunkin K, Zuber J, James T, Khan AA, Leslie CS, Parker JS, Paddison PJ, Tam W, Ferrando A, and Wendel HG
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation, Cell Survival, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Gene Knockdown Techniques, Gene Rearrangement, T-Lymphocyte, Genome-Wide Association Study, Mice, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology, Receptor, Notch1 metabolism, Signal Transduction genetics, Time Factors, Transduction, Genetic, Translocation, Genetic, Gene Expression Regulation, Leukemic, MicroRNAs metabolism, Oncogenes, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, RNA Interference, Receptor, Notch1 genetics
- Abstract
MicroRNAs (miRNAs) have emerged as novel cancer genes. In particular, the miR-17-92 cluster, containing six individual miRNAs, is highly expressed in haematopoietic cancers and promotes lymphomagenesis in vivo. Clinical use of these findings hinges on isolating the oncogenic activity within the 17-92 cluster and defining its relevant target genes. Here we show that miR-19 is sufficient to promote leukaemogenesis in Notch1-induced T-cell acute lymphoblastic leukaemia (T-ALL) in vivo. In concord with the pathogenic importance of this interaction in T-ALL, we report a novel translocation that targets the 17-92 cluster and coincides with a second rearrangement that activates Notch1. To identify the miR-19 targets responsible for its oncogenic action, we conducted a large-scale short hairpin RNA screen for genes whose knockdown can phenocopy miR-19. Strikingly, the results of this screen were enriched for miR-19 target genes, and include Bim (Bcl2L11), AMP-activated kinase (Prkaa1) and the phosphatases Pten and PP2A (Ppp2r5e). Hence, an unbiased, functional genomics approach reveals a coordinate clampdown on several regulators of phosphatidylinositol-3-OH kinase-related survival signals by the leukaemogenic miR-19.
- Published
- 2010
- Full Text
- View/download PDF
45. Endogenous reverse transcriptase as a mediator of ursolic acid's anti-proliferative and differentiating effects in human cancer cell lines.
- Author
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Bonaccorsi I, Altieri F, Sciamanna I, Oricchio E, Grillo C, Contartese G, and Galati EM
- Subjects
- Cell Line, Tumor, Fluorescent Antibody Technique, Indirect, Humans, Reverse Transcriptase Polymerase Chain Reaction, Ursolic Acid, Cell Differentiation drug effects, Cell Proliferation drug effects, RNA-Directed DNA Polymerase metabolism, Triterpenes pharmacology
- Abstract
Ursolic acid (UA) is a pentacyclic triterpenoid compound that is widely distributed in the plant kingdom and has a broad range of biological effects. Here, we examined the effects of UA on the proliferation and differentiation of human tumor cell lines from melanoma (A375), glioblastoma (U87) and thyroid anaplastic carcinoma (ARO), and on the proliferation of a non-transformed human fibroblast cell line (WI-38). The results show that UA inhibits tumor cell proliferation in a dose- and time-dependent manner. Consistent with this finding, UA treatment promotes differentiation of all of the analyzed tumor cell lines. Interestingly, we found that UA inhibits the endogenous reverse transcriptase (RT) activity in tumor cells, which has recently been shown to be involved in the control of proliferation and differentiation of neoplastic cells. Considering these findings, we suggest that the observed anti-proliferative and differentiating effects of UA may be related to this target.
- Published
- 2008
- Full Text
- View/download PDF
46. ATM is activated by default in mitosis, localizes at centrosomes and monitors mitotic spindle integrity.
- Author
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Oricchio E, Saladino C, Iacovelli S, Soddu S, and Cundari E
- Subjects
- Ataxia Telangiectasia, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins genetics, Cell Line, DNA-Binding Proteins genetics, Humans, Mutation genetics, Phosphoserine metabolism, Protein Serine-Threonine Kinases genetics, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Proteins genetics, Cell Cycle Proteins metabolism, Centrosome metabolism, DNA-Binding Proteins metabolism, Mitosis, Protein Serine-Threonine Kinases metabolism, Spindle Apparatus metabolism, Tumor Suppressor Proteins metabolism
- Abstract
We previously showed that ATM is responsible for p53 phosphorylation at Ser15 and localization at centrosomes during mitosis. When p53 centrosomal localization is prevented by inhibiting polymerization of spindle microtubules, a stabilized form of p53 is transmitted to daughter cells that arrest in the next G(1) phase of the cell cycle after exit from mitosis. AT cells are unable to both localize p53 at centrosomes in mitosis and arrest after exposure to mitotic-spindle poisons. Here we show that during mitosis ATM is activated by phosphorylation at Ser1981 and localizes at centrosomes. When mitotic spindle is disrupted by nocodazole, ATM is displaced from centrosomes and colocalizes with phospho-Ser15-p53 under the form of spots dispersed in the mitotic cytoplasm. After release from nocodazole-block, as soon as cells exit mitosis, p53 is redirected to the nucleus and its Ser15 phosphorylation is substituted by phosphorylation at Ser46. We suggest that ATM is activated by default at each mitotic onset and phosphorylates p53 at Ser15 so as to keep it inactive at centrosomes when the spindle is correctly in place or, in case of inactivation of the mitotic spindle, to maintain the memory of a perturbed mitosis.
- Published
- 2006
- Full Text
- View/download PDF
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