22 results on '"Possik PA"'
Search Results
2. Gene expression profile of human Down syndrome leukocytes
- Author
-
Malago, W., Sommer, Ca, Andrade, Cd, Soares-Costa, A., Possik, Pa, Cassago, A., Silveira, Hcs, and Henrique Silveira
3. Acral melanoma: new insights into the immune and genomic landscape.
- Author
-
Carvalho LAD, Aguiar FC, Smalley KSM, and Possik PA
- Subjects
- Humans, Ultraviolet Rays adverse effects, Genomics, Melanoma, Cutaneous Malignant, Melanoma genetics, Melanoma drug therapy, Skin Neoplasms genetics, Skin Neoplasms drug therapy
- Abstract
Acral melanoma is a rare subtype of melanoma that arises on the non-hair bearing skin of the nail bed, palms of the hand and soles of the feet. It is unique among melanomas in not being linked to ultraviolet radiation (UVR) exposure from the sun, and, as such, its incidence is similar across populations who are of Asian, Hispanic, African and European origin. Although research into acral melanoma has lagged behind that of sun-exposed cutaneous melanoma, recent studies have begun to address the unique genetics and immune features of acral melanoma. In this review we will discuss the latest progress in understanding the biology of acral melanoma across different ethnic populations and will outline how these new discoveries can help to guide the therapeutic management of this rare tumor., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)
- Published
- 2023
- Full Text
- View/download PDF
4. Obstacles and opportunities in studying melanoma in Latin America.
- Author
-
Possik PA
- Subjects
- Humans, Latin America epidemiology, Research, Melanoma diagnosis, Melanoma epidemiology, Melanoma therapy
- Published
- 2023
- Full Text
- View/download PDF
5. Mutually exclusive genetic interactions and gene essentiality shape the genomic landscape of primary melanoma.
- Author
-
Birkeälv S, Harland M, Matsuyama LSAS, Rashid M, Mehta I, Laye JP, Haase K, Mell T, Iyer V, Robles-Espinoza CD, McDermott U, van Loo P, Kuijjer ML, Possik PA, Maria Engler SS, Bishop DT, Newton-Bishop J, and Adams DJ
- Subjects
- Humans, Mutation, Genome, Genomics, United Kingdom, Melanoma genetics
- Abstract
Melanoma is a heterogenous malignancy with an unpredictable clinical course. Most patients who present in the clinic are diagnosed with primary melanoma, yet large-scale sequencing efforts have focused primarily on metastatic disease. In this study we sequence-profiled 524 American Joint Committee on Cancer Stage I-III primary tumours. Our analysis of these data reveals recurrent driver mutations, mutually exclusive genetic interactions, where two genes were never or rarely co-mutated, and an absence of co-occurring genetic events. Further, we intersected copy number calls from our primary melanoma data with whole-genome CRISPR screening data to identify the transcription factor interferon regulatory factor 4 (IRF4) as a melanoma-associated dependency. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)
- Published
- 2023
- Full Text
- View/download PDF
6. Pro-Apoptotic Antitumoral Effect of Novel Acridine-Core Naphthoquinone Compounds against Oral Squamous Cell Carcinoma.
- Author
-
Zorzanelli BC, Ouverney G, Pauli FP, da Fonseca ACC, de Almeida ECP, de Carvalho DG, Possik PA, Rabelo VW, Abreu PA, Pontes B, Ferreira VF, Forezi LDSM, da Silva FC, and Robbs BK
- Subjects
- Acridines pharmacology, Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Molecular Docking Simulation, Squamous Cell Carcinoma of Head and Neck drug therapy, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell pathology, Head and Neck Neoplasms drug therapy, Mouth Neoplasms drug therapy, Mouth Neoplasms pathology, Naphthoquinones pharmacology, Naphthoquinones therapeutic use
- Abstract
Oral squamous cell carcinoma (OSCC) is a global public health problem with high incidence and mortality. The chemotherapeutic agents used in the clinic, alone or in combination, usually lead to important side effects. Thus, the discovery and development of new antineoplastic drugs are essential to improve disease prognosis and reduce toxicity. In the present study, acridine-core naphthoquinone compounds were synthesized and evaluated for their antitumor activity in OSCC cells. The mechanism of action, pharmacokinetics, and toxicity parameters of the most promising compound was further analyzed using in silico, in vitro, and in vivo methods. Among the derivatives, compound 4e was highly cytotoxic (29.99 µM) and selective (SI 2.9) at levels comparable and generally superior to chemotherapeutic controls. Besides, compound 4e proved to be non-hemolytic, stable, and well tolerated in animals at all doses tested. Mechanistically, compound 4e promoted cell death by apoptosis in the OSCC cell, and molecular docking studies suggested this compound possibly targets enzymes important for tumor progression, such as RSK2, PKM2, and topoisomerase IIα. Importantly, compound 4e presented a pharmacological profile within desirable parameters for drug development, showing promise for future preclinical trials.
- Published
- 2022
- Full Text
- View/download PDF
7. TOP1 modulation during melanoma progression and in adaptative resistance to BRAF and MEK inhibitors.
- Author
-
Oliveira ÉA, Chauhan J, Silva JRD, Carvalho LADC, Dias D, Carvalho DG, Watanabe LRM, Rebecca VW, Mills G, Lu Y, da Silva ASF, Consolaro MEL, Herlyn M, Possik PA, Goding CR, and Maria-Engler SS
- Subjects
- Antineoplastic Agents therapeutic use, Cell Line, Tumor, Disease Progression, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins B-raf antagonists & inhibitors, DNA Topoisomerases, Type I genetics, DNA Topoisomerases, Type I metabolism, Drug Resistance, Neoplasm, Melanoma drug therapy, Melanoma genetics, Melanoma metabolism, Melanoma mortality, Skin Neoplasms drug therapy, Skin Neoplasms genetics, Skin Neoplasms metabolism, Skin Neoplasms mortality
- Abstract
In melanomas, therapy resistance can arise due to a combination of genetic, epigenetic and phenotypic mechanisms. Due to its crucial role in DNA supercoil relaxation, TOP1 is often considered an essential chemotherapeutic target in cancer. However, how TOP1 expression and activity might differ in therapy sensitive versus resistant cell types is unknown. Here we show that TOP1 expression is increased in metastatic melanoma and correlates with an invasive gene expression signature. More specifically, TOP1 expression is highest in cells with the lowest expression of MITF, a key regulator of melanoma biology. Notably, TOP1 and DNA Single-Strand Break Repair genes are downregulated in BRAFi- and BRAFi/MEKi-resistant cells and TOP1 inhibition decreases invasion markers only in BRAFi/MEKi-resistant cells. Thus, we show three different phenotypes related to TOP1 levels: i) non-malignant cells with low TOP1 levels; ii) metastatic cells with high TOP1 levels and high invasiveness; and iii) BRAFi- and BRAFi/MEKi-resistant cells with low TOP1 levels and high invasiveness. Together, these results highlight the potential role of TOP1 in melanoma progression and resistance., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
8. More than just acral melanoma: the controversies of defining the disease.
- Author
-
Bernardes SS, Ferreira I, Elder DE, Nobre AB, Martínez-Said H, Adams DJ, Robles-Espinoza CD, and Possik PA
- Subjects
- Animals, Biomarkers, Tumor genetics, Foot pathology, Hand pathology, Humans, Nails pathology, Prognosis, Melanoma epidemiology, Melanoma genetics, Melanoma pathology, Skin Neoplasms epidemiology, Skin Neoplasms genetics, Skin Neoplasms pathology
- Abstract
Acral melanoma (AM) is a malignant cutaneous melanocytic tumour specifically located on the palms, soles, and nail apparatus, which are areas of glabrous (hairless) skin. Acral lentiginous melanoma, a subtype of AM, represents a histopathological subtype diagnosis of cutaneous melanoma with unique morphological and structural features. Despite clear definitions, the misuse of these terms and the inconsistency in reporting the histopathological features of AM cases have become a major obstacle to the study of the disease. In this review, we discuss the epidemiology, histopathological features, prognosis, and genetic profile of AM, highlighting the differences observed when histopathological subtypes are considered. The increasing global effort to characterise AM cases from ethnically diverse populations would benefit greatly from a more consistent classification of the disease., (© 2021 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland & John Wiley & Sons, Ltd.)
- Published
- 2021
- Full Text
- View/download PDF
9. Acral lentiginous melanoma: Basic facts, biological characteristics and research perspectives of an understudied disease.
- Author
-
Basurto-Lozada P, Molina-Aguilar C, Castaneda-Garcia C, Vázquez-Cruz ME, Garcia-Salinas OI, Álvarez-Cano A, Martínez-Said H, Roldán-Marín R, Adams DJ, Possik PA, and Robles-Espinoza CD
- Subjects
- Humans, Foot Diseases pathology, Melanocytes pathology, Melanoma pathology, Nail Diseases pathology, Skin Neoplasms pathology
- Abstract
Acral lentiginous melanoma is a histological subtype of cutaneous melanoma that occurs in the glabrous skin of the palms, soles and the nail unit. Although in some countries, particularly in Latin America, Africa and Asia, it represents the most frequently diagnosed subtype of the disease, it only represents a small proportion of melanoma cases in European-descent populations, which is partially why it has not been studied to the same extent as other forms of melanoma. As a result, its unique genomic drivers remain comparatively poorly explored, as well as its causes, with current evidence supporting a UV-independent path to tumorigenesis. In this review, we discuss current knowledge of the aetiology and diagnostic criteria of acral lentiginous melanoma, as well as its epidemiological and histopathological characteristics. We also describe what is known about the genomic landscape of this disease and review the available biological models to explore potential therapeutic targets., (© 2020 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)
- Published
- 2021
- Full Text
- View/download PDF
10. Extracellular vesicle-mediated crosstalk between melanoma and the immune system: Impact on tumor progression and therapy response.
- Author
-
Pretti MAM, Bernardes SS, da Cruz JGV, Boroni M, and Possik PA
- Subjects
- Extracellular Vesicles pathology, Humans, Melanoma pathology, Melanoma therapy, Neoplasm Metastasis, Biomarkers, Tumor immunology, Cell Communication immunology, Cell Proliferation, Extracellular Vesicles immunology, Melanoma immunology, Tumor Microenvironment immunology
- Abstract
Melanoma is a very lethal tumor type that easily spreads and colonizes regional and distant tissues. Crucial phenotypic changes that favor melanoma metastasis are interposed by the tumor microenvironment (TME), representing a complex network in which malignant cells communicate not only with each other but also with stromal and immune cells. This cell-cell communication can be mediated by extracellular vesicles (EVs), which are lipid bilayer-delimited particles capable of carrying a wide variety of bioactive compounds. Both melanoma-derived or TME-derived EVs deliver important pro- and antitumor signals implicated in various stages of tumor progression, such as proliferation, metastasis, and treatment response. In this review, we highlight the recent advances in EV-mediated crosstalk between melanoma and immune cells and other important cells of the TME, and address different aspects of this bidirectional interaction as well as how this may hinder or trigger the development and progression of melanoma. We also discuss the potential of using EVs as biomarkers and therapeutic strategies for melanoma., (©2020 Society for Leukocyte Biology.)
- Published
- 2020
- Full Text
- View/download PDF
11. Poor clinical outcome in metastatic melanoma is associated with a microRNA-modulated immunosuppressive tumor microenvironment.
- Author
-
Jorge NAN, Cruz JGV, Pretti MAM, Bonamino MH, Possik PA, and Boroni M
- Subjects
- Humans, Prognosis, Transcriptome, Tumor Microenvironment, Melanoma genetics, MicroRNAs genetics
- Abstract
Background: Interaction between malignant cells and immune cells that reside within the tumor microenvironment (TME) modulate different aspects of tumor development and progression. Recent works showed the importance of miRNA-containing extracellular vesicles in this crosstalk., Methods: Interested in understanding the interplay between melanoma and immune-related TME cells, we characterized the TCGA's metastatic melanoma samples according to their tumor microenvironment profiles, HLA-I neoepitopes, transcriptome profile and classified them into three groups. Moreover, we combined our results with melanoma single-cell gene expression and public miRNA data to better characterize the regulatory network of circulating miRNAs and their targets related to immune evasion and microenvironment response., Results: The group associated with a worse prognosis showed phenotypic characteristics that favor immune evasion, including a strong signature of suppressor cells and less stable neoantigen:HLA-I complexes. Conversely, the group with better prognosis was marked by enrichment in lymphocyte and MHC signatures. By analyzing publicly available melanoma single-cell RNA and microvesicle microRNAs sequencing data we identified circulating microRNAs potentially involved in the crosstalk between tumor and TME cells. Candidate miRNA/target gene pairs with previously reported roles in tumor progression and immune escape mechanisms were further investigated and demonstrated to impact patient's overall survival not only in melanoma but across different tumor types., Conclusion: Our results underscore the impact of tumor-microenvironment interactions on disease outcomes and reveal potential non-invasive biomarkers of prognosis and treatment response.
- Published
- 2020
- Full Text
- View/download PDF
12. Protease-activated receptor 2 (PAR2) upregulates granulocyte colony stimulating factor (G-CSF) expression in breast cancer cells.
- Author
-
Carvalho É, Hugo de Almeida V, Rondon AMR, Possik PA, Viola JPB, and Monteiro RQ
- Subjects
- Animals, Cell Line, Tumor, Cytokines metabolism, Female, Gene Expression Profiling, HEK293 Cells, Humans, Mice, Transcriptional Activation, Up-Regulation, Breast Neoplasms metabolism, Gene Expression Regulation, Neoplastic, Granulocyte Colony-Stimulating Factor metabolism, Receptor, PAR-2 metabolism, Receptors, G-Protein-Coupled metabolism
- Abstract
Protease-activated receptor 2 (PAR2) is a G-protein coupled receptor which is activated upon cleavage of its N-terminal region. PAR2 has been associated with many aspects regarding tumor progression, such as the production of pro-tumoral cytokines. Granulocyte colony-stimulating factor (G-CSF) is a cytokine essential to neutrophil production and maturation, and it is often overexpressed in tumors. In this study, we evaluated the ability of PAR2 to modulate G-CSF expression. PAR2 and G-CSF were significantly more expressed in metastatic (4T1 and MDA-MB-231) as compared to non-metastatic (67NR and MCF7) breast cancer cell lines. In addition, PAR2 stimulation by a synthetic agonist peptide significantly increased G-CSF gene expression in the metastatic cell lines. Knockdown of PAR2 in 4T1 cells decreased G-CSF expression and secretion. In addition, treatment of 4T1 with the commercial PAR2 antagonist, ENMD-1068, significantly decreased G-CSF expression. cBioPortal analyses of the TCGA database showed a significant co-occurrence of G-CSF and PAR2 gene overexpression in breast cancer samples. In conclusion, our data suggest that PAR2 contributes to G-CSF expression in breast cancer cells, possibly favoring tumor progression., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
13. Integrated in vivo genetic and pharmacologic screening identifies co-inhibition of EGRF and ROCK as a potential treatment regimen for triple-negative breast cancer.
- Author
-
Iskit S, Lieftink C, Halonen P, Shahrabi A, Possik PA, Beijersbergen RL, and Peeper DS
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation genetics, Drug Synergism, ErbB Receptors genetics, ErbB Receptors metabolism, Female, HEK293 Cells, Humans, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, RNA Interference, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms metabolism, rho-Associated Kinases genetics, rho-Associated Kinases metabolism, ErbB Receptors antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Triple Negative Breast Neoplasms drug therapy, Xenograft Model Antitumor Assays methods, rho-Associated Kinases antagonists & inhibitors
- Abstract
Breast cancer is the second most common cause of cancer-related deaths worldwide among women. Despite several therapeutic options, 15% of breast cancer patients succumb to the disease owing to tumor relapse and acquired therapy resistance. Particularly in triple-negative breast cancer (TNBC), developing effective treatments remains challenging owing to the lack of a common vulnerability that can be exploited by targeted approaches. We have previously shown that tumor cells have different requirements for growth in vivo than in vitro. Therefore, to discover novel drug targets for TNBC, we performed parallel in vivo and in vitro genetic shRNA dropout screens. We identified several potential drug targets that were required for tumor growth in vivo to a greater extent than in vitro. By combining pharmacologic inhibitors acting on a subset of these candidates, we identified a synergistic interaction between EGFR and ROCK inhibitors. This combination effectively reduced TNBC cell growth by inducing cell cycle arrest. These results illustrate the power of in vivo genetic screens and warrant further validation of EGFR and ROCK as combined pharmacologic targets for breast cancer., Competing Interests: No conflicts of interest to declare.
- Published
- 2016
- Full Text
- View/download PDF
14. PhosphoPath: Visualization of Phosphosite-centric Dynamics in Temporal Molecular Networks.
- Author
-
Raaijmakers LM, Giansanti P, Possik PA, Mueller J, Peeper DS, Heck AJ, and Altelaar AF
- Subjects
- Cell Line, Tumor, Computer Graphics, Gene Regulatory Networks, Humans, Melanoma genetics, Melanoma pathology, Phosphoproteins genetics, Phosphoproteins isolation & purification, Phosphorylation, Proteome genetics, Proteome isolation & purification, Proteomics, Skin Neoplasms genetics, Skin Neoplasms pathology, Tandem Mass Spectrometry, Melanoma metabolism, Mobile Applications, Phosphoproteins metabolism, Protein Processing, Post-Translational, Proteome metabolism, Skin Neoplasms metabolism
- Abstract
Protein phosphorylation is an essential post-translational modification (PTM) regulating many biological processes at the cellular and multicellular level. Continuous improvements in phosphoproteomics technology allow the analysis of this PTM in an expanding biological content, yet up until now proteome data visualization tools are still very gene centric, hampering the ability to comprehensively map and study PTM dynamics. Here we present PhosphoPath, a Cytoscape app designed for the visualization and analysis of quantitative proteome and phosphoproteome data sets. PhosphoPath brings knowledge into the biological network by importing publically available data and enables PTM site-specific visualization of information from quantitative time series. To showcase PhosphoPath performance we use a quantitative proteomics data set comparing patient-derived melanoma cell lines grown in either conventional cell culture or xenografts.
- Published
- 2015
- Full Text
- View/download PDF
15. Cooperative induction of apoptosis in NRAS mutant melanoma by inhibition of MEK and ROCK.
- Author
-
Vogel CJ, Smit MA, Maddalo G, Possik PA, Sparidans RW, van der Burg SH, Verdegaal EM, Heck AJ, Samatar AA, Beijnen JH, Altelaar AF, and Peeper DS
- Subjects
- Cell Line, Tumor, Humans, Melanoma enzymology, Mitogen-Activated Protein Kinase Kinases metabolism, Protein Kinase Inhibitors pharmacology, Proteome metabolism, rho-Associated Kinases metabolism, Apoptosis drug effects, GTP Phosphohydrolases genetics, Melanoma pathology, Membrane Proteins genetics, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Mutation genetics, rho-Associated Kinases antagonists & inhibitors
- Abstract
No effective targeted therapy is currently available for NRAS mutant melanoma. Experimental MEK inhibition is rather toxic and has only limited efficacy in clinical trials. At least in part, this is caused by the emergence of drug resistance, which is commonly seen for single agent treatment and shortens clinical responses. Therefore, there is a dire need to identify effective companion drug targets for NRAS mutant melanoma. Here, we show that at concentrations where single drugs had little effect, ROCK inhibitors GSK269962A or Fasudil, in combination with either MEK inhibitor GSK1120212 (Trametinib) or ERK inhibitor SCH772984 cooperatively caused proliferation inhibition and cell death in vitro. Simultaneous inhibition of MEK and ROCK caused induction of BimEL , PARP, and Puma, and hence apoptosis. In vivo, MEK and ROCK inhibition suppressed growth of established tumors. Our findings warrant clinical investigation of the effectiveness of combinatorial targeting of MAPK/ERK and ROCK in NRAS mutant melanoma., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2015
- Full Text
- View/download PDF
16. ROCK1 is a potential combinatorial drug target for BRAF mutant melanoma.
- Author
-
Smit MA, Maddalo G, Greig K, Raaijmakers LM, Possik PA, van Breukelen B, Cappadona S, Heck AJ, Altelaar AF, and Peeper DS
- Subjects
- Cell Line, Tumor, Chromatography, Liquid, Down-Regulation, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Humans, Indazoles pharmacology, Indoles pharmacology, Molecular Targeted Therapy, Mutation, Piperazines pharmacology, Proteomics, Proto-Oncogene Proteins B-raf genetics, RNA Interference, RNA, Small Interfering genetics, Receptor, ErbB-3 genetics, Receptor, ErbB-3 metabolism, Sulfonamides pharmacology, Tandem Mass Spectrometry, Vemurafenib, rho-Associated Kinases genetics, Melanoma genetics, Proto-Oncogene Proteins B-raf metabolism, rho-Associated Kinases metabolism
- Abstract
Treatment of BRAF mutant melanomas with specific BRAF inhibitors leads to tumor remission. However, most patients eventually relapse due to drug resistance. Therefore, we designed an integrated strategy using (phospho)proteomic and functional genomic platforms to identify drug targets whose inhibition sensitizes melanoma cells to BRAF inhibition. We found many proteins to be induced upon PLX4720 (BRAF inhibitor) treatment that are known to be involved in BRAF inhibitor resistance, including FOXD3 and ErbB3. Several proteins were down-regulated, including Rnd3, a negative regulator of ROCK1 kinase. For our genomic approach, we performed two parallel shRNA screens using a kinome library to identify genes whose inhibition sensitizes to BRAF or ERK inhibitor treatment. By integrating our functional genomic and (phospho)proteomic data, we identified ROCK1 as a potential drug target for BRAF mutant melanoma. ROCK1 silencing increased melanoma cell elimination when combined with BRAF or ERK inhibitor treatment. Translating this to a preclinical setting, a ROCK inhibitor showed augmented melanoma cell death upon BRAF or ERK inhibition in vitro. These data merit exploration of ROCK1 as a target in combination with current BRAF mutant melanoma therapies., (© 2014 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2014
- Full Text
- View/download PDF
17. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma.
- Author
-
Müller J, Krijgsman O, Tsoi J, Robert L, Hugo W, Song C, Kong X, Possik PA, Cornelissen-Steijger PD, Geukes Foppen MH, Kemper K, Goding CR, McDermott U, Blank C, Haanen J, Graeber TG, Ribas A, Lo RS, and Peeper DS
- Subjects
- Aminopyridines pharmacology, Animals, Benzamides pharmacology, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases genetics, Extracellular Signal-Regulated MAP Kinases metabolism, Humans, Imatinib Mesylate, Imidazoles pharmacology, Indoles pharmacology, Melanoma genetics, Melanoma metabolism, Melanoma pathology, Mice, Microphthalmia-Associated Transcription Factor metabolism, Oximes pharmacology, Piperazines pharmacology, Prognosis, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf metabolism, Pyridones pharmacology, Pyrimidines pharmacology, Pyrimidinones pharmacology, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Receptor Protein-Tyrosine Kinases metabolism, Signal Transduction, Skin Neoplasms genetics, Skin Neoplasms metabolism, Skin Neoplasms pathology, Sulfonamides pharmacology, Vemurafenib, Xenograft Model Antitumor Assays, Axl Receptor Tyrosine Kinase, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm genetics, Gene Expression Regulation, Neoplastic, Melanoma drug therapy, Microphthalmia-Associated Transcription Factor genetics, Proto-Oncogene Proteins genetics, Receptor Protein-Tyrosine Kinases genetics, Skin Neoplasms drug therapy
- Abstract
Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.
- Published
- 2014
- Full Text
- View/download PDF
18. [Have you eaten any DNA today? Science communication during Science and Technology Week in Brazil].
- Author
-
Possik PA, Shumiski LC, Corrêa EM, Maia Rde A, Medaglia A, Mourão LP, Pereira JM, Persuhn DC, Rufier M, Santos M, Sobreira M, and Elblink MT
- Abstract
During the first National Science and Technology Week held in 2004, science centers and museums, universities and schools engaged in activities with the idea of divulging science to the people. Demonstrations of the extraction of DNA from fruits were conducted in supermarkets in 11 Brazilian cities by two institutions, DNA Vai à Escola and Conselho de Informação e Biotecnologia. This article describes the formation of a national network of people interested in communicating information about genetics to the lay public and the implementation of a low-cost science communication activity in different parts of the country simultaneously. It also analyzes the impact caused by this initiative and the perceptions of those involved in its organization.
- Published
- 2013
- Full Text
- View/download PDF
19. Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis.
- Author
-
Vredeveld LC, Possik PA, Smit MA, Meissl K, Michaloglou C, Horlings HM, Ajouaou A, Kortman PC, Dankort D, McMahon M, Mooi WJ, and Peeper DS
- Subjects
- Amino Acid Substitution, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p15 metabolism, Enzyme Activation, Fibroblasts metabolism, Fibroblasts pathology, Glutamic Acid genetics, Glutamic Acid metabolism, Humans, Melanocytes metabolism, Melanocytes pathology, Melanoma metabolism, Nevus metabolism, PTEN Phosphohydrolase genetics, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins c-akt metabolism, Skin Neoplasms metabolism, Valine genetics, Valine metabolism, Cellular Senescence, Melanoma pathology, Nevus pathology, PTEN Phosphohydrolase metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins B-raf metabolism, Skin Neoplasms pathology
- Abstract
Human melanocytic nevi (moles) are benign lesions harboring activated oncogenes, including BRAF. Although this oncogene initially acts mitogenically, eventually, oncogene-induced senescence (OIS) ensues. Nevi can infrequently progress to melanomas, but the mechanistic relationship with OIS is unclear. We show here that PTEN depletion abrogates BRAF(V600E)-induced senescence in human fibroblasts and melanocytes. Correspondingly, in established murine BRAF(V600E)-driven nevi, acute shRNA-mediated depletion of PTEN prompted tumor progression. Furthermore, genetic analysis of laser-guided microdissected human contiguous nevus-melanoma specimens recurrently revealed identical mutations in BRAF or NRAS in adjacent benign and malignant melanocytes. The PI3K pathway was often activated through either decreased PTEN or increased AKT3 expression in melanomas relative to their adjacent nevi. Pharmacologic PI3K inhibition in melanoma cells suppressed proliferation and induced the senescence-associated tumor suppressor p15(INK4B). This treatment also eliminated subpopulations resistant to targeted BRAF(V600E) inhibition. Our findings suggest that a significant proportion of melanomas arise from nevi. Furthermore, these results demonstrate that PI3K pathway activation serves as a rate-limiting event in this setting, acting at least in part by abrogating OIS. The reactivation of senescence features and elimination of cells refractory to BRAF(V600E) inhibition by PI3K inhibition warrants further investigation into the therapeutic potential of simultaneously targeting these pathways in melanoma.
- Published
- 2012
- Full Text
- View/download PDF
20. Evidence of oncogene-induced senescence in thyroid carcinogenesis.
- Author
-
Vizioli MG, Possik PA, Tarantino E, Meissl K, Borrello MG, Miranda C, Anania MC, Pagliardini S, Seregni E, Pierotti MA, Pilotti S, Peeper DS, and Greco A
- Subjects
- Adult, Aged, Carcinoma, Carcinoma, Papillary, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p16 biosynthesis, Cyclin-Dependent Kinase Inhibitor p21 biosynthesis, Female, HEK293 Cells, Humans, Insulin-Like Growth Factor Binding Proteins biosynthesis, Male, Middle Aged, Thyroid Cancer, Papillary, Thyroid Carcinoma, Anaplastic, Thyroid Gland cytology, Transduction, Genetic, Aging, Proto-Oncogenes genetics, Thyroid Neoplasms metabolism
- Abstract
Oncogene-induced senescence (OIS) is a growth arrest triggered by the enforced expression of cancer-promoting genes and acts as a barrier against malignant transformation in vivo. In this study, by a combination of in vitro and in vivo approaches, we investigate the role of OIS in tumours originating from the thyroid epithelium. We found that expression of different thyroid tumour-associated oncogenes in primary human thyrocytes triggers senescence, as demonstrated by the presence of OIS hallmarks: changes in cell morphology, accumulation of SA-β-Gal and senescence-associated heterochromatic foci, and upregulation of transcription of the cyclin-dependent kinase inhibitors p16(INK4a) and p21(CIP1). Furthermore, immunohistochemical analysis of a panel of thyroid tumours characterised by different aggressiveness showed that the expression of OIS markers such as p16(INK4a), p21(CIP1) and IGFBP7 is upregulated at early stages, and lost during thyroid tumour progression. Taken together, our results suggest a role of OIS in thyroid carcinogenesis.
- Published
- 2011
- Full Text
- View/download PDF
21. If you can't beat me, join me: collaborating oncogenes circumventing senescence and causing cancer.
- Author
-
Possik PA and Peeper DS
- Subjects
- Animals, Cell Proliferation, Cell Transformation, Neoplastic, Gene Expression Regulation, Neoplastic, Humans, Mice, Neoplasms genetics, PTEN Phosphohydrolase genetics, PTEN Phosphohydrolase metabolism, Pancreatic Neoplasms genetics, Phosphatidylinositol 3-Kinase metabolism, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Cellular Senescence genetics, Oncogenes genetics, Phosphatidylinositol 3-Kinase genetics
- Published
- 2011
- Full Text
- View/download PDF
22. DSCR2, a Down syndrome critical region protein, is localized to the endoplasmic reticulum of mammalian cells.
- Author
-
Possik PA, Sommer CA, Issa Hori J, Machado-Santelli GM, Jamur MC, and Henrique-Silva F
- Subjects
- Animals, CHO Cells, COS Cells, Cell Line, Chlorocebus aethiops, Cricetinae, Endoplasmic Reticulum ultrastructure, Gene Expression Regulation, Developmental, Green Fluorescent Proteins genetics, Humans, Immunohistochemistry, Membrane Proteins genetics, Membrane Proteins ultrastructure, Molecular Chaperones, Muscle Proteins genetics, Muscle Proteins ultrastructure, Mutagenesis, Site-Directed, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Sequence Deletion, Down Syndrome genetics, Endoplasmic Reticulum metabolism, Membrane Proteins metabolism, Muscle Proteins metabolism
- Abstract
We used immunocytochemical and fluorescence assays to investigate the subcellular location of the protein encoded by Down syndrome critical region gene 2 (DSCR2) in transfected cells. It was previously suggested that DSCR2 is located in the plasma membrane as an integral membrane protein. Interestingly, we observed this protein in the endoplasmic reticulum (ER) of cells. We also studied whether the truncated forms of DSCR2 showed different subcellular distributions. Our observations indicate that DSCR2 probably is not inserted into the membrane of the endoplasmic reticulum since the fragments lacking the predicted transmembrane (TM) helices remained associated with the ER. Our analyses suggest that, although DSCR2 is associated with the endoplasmic reticulum, it is not an integral membrane protein and it is maintained on the cytoplasmic side of the ER by indirect interaction with the ER membrane or with another protein.
- Published
- 2004
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.