| 1. |
- Azimi, Alireza, et al.
(författare)
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Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors
- 2018
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Ingår i: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 14:3
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Tidskriftsartikel (refereegranskat)abstract
- Novel therapies are undergoing clinical trials, for example, the Hsp90 inhibitor, XL888, in combination with BRAF inhibitors for the treatment of therapy-resistant melanomas. Unfortunately, our data show that this combination elicits a heterogeneous response in a panel of melanoma cell lines including PDX-derived models. We sought to understand the mechanisms underlying the differential responses and suggest a patient stratification strategy. Thermal proteome profiling (TPP) identified the protein targets of XL888 in a pair of sensitive and unresponsive cell lines. Unbiased proteomics and phosphoproteomics analyses identified CDK2 as a driver of resistance to both BRAF and Hsp90 inhibitors and its expression is regulated by the transcription factor MITF upon XL888 treatment. The CDK2 inhibitor, dinaciclib, attenuated resistance to both classes of inhibitors and combinations thereof. Notably, we found that MITF expression correlates with CDK2 upregulation in patients; thus, dinaciclib would warrant consideration for treatment of patients unresponsive to BRAF-MEK and/or Hsp90 inhibitors and/or harboring MITF amplification/overexpression.
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| 2. |
- Caramuta, Stefano
(författare)
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Clinical and functional aspects of microRNA regulation in human cancers
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- miRNAs are short single-stranded non-coding RNAs which regulate gene expression at the post-transcriptional level in many biological processes, including proliferation, apoptosis and differentiation. A number of studies have shown the importance of miRNAs in carcinogenesis and accumulating evidence supports their role as diagnostic and prognostic biomarkers in human cancers. Moreover, dysregulation of miRNA processing factors, which are needed for miRNA maturation, have been recently shown to play an important role in tumor initiation and progression and to have a prognostic potential in different types of cancer. Despite all the achievements, our knowledge of the biological role of miRNAs and miRNA processing pathway in tumor development and progression is still in its infancy. The general purpose of this thesis was to improve our understanding of the clinical and functional implications of miRNA deregulation in human cancer. In paper I, we reported frequent deregulation of miRNA expression in lymph node metastases of malignant melanoma and melanoma cell lines as compared to normal melanocytes and showed its association to BRAF and NRAS mutational status. Moreover, we identified a two-miRNA signature that could predict survival in metastatic melanoma patients. In paper II, we performed genome-wide miRNA expression profiling of adrenocortical tumors and identified distinct miRNA expression patterns in adrenocortical carcinomas (ACC) compared to adenomas and normal adrenal cortices. Over-expression of miR- 483-3p/-5p and down-regulation of miR-195 and miR-497 were the most common features of ACC. We also elucidated the functional consequences of deregulation of these 4 miRNAs on cell proliferation and apoptosis in ACC cells and, in addition, we demonstrated the potential involvement of the pro-apoptotic factor PUMA (a target of miR-483-3p) in adrenocortical tumors. Moreover, we found novel miRNAs associated with short survival in ACC. In paper III, we evaluated the expression and the potential role of the main components of the miRNA machinery in adrenocortical tumors. We observed frequent over-expression of TRBP2 in ACC and found that TRBP2 mRNA expression level is a reliable predictor of carcinoma among adrenocortical tumors. These data suggest that TRBP2 may be a novel and sensitive biomarker for adrenocortical tumors. Functionally, we unraveled the potential oncogenic role of TRBP2 in ACC and identified some of the molecular mechanisms involved in the regulation of TRBP2 expression in this tumor type. In paper IV, we analyzed the expression of miRNAs and miRNA machinery factors in diffuse large B-cell lymphoma (DLBCL). We identified miRNA signatures that could discriminate DLBCL tumors from non-neoplastic tissue and found subsets of miRNAs able to classify DLBCL sub-types. Moreover, we showed dysregulation of miRNA machinery factors in DLBCL and demonstrated that it could influence miRNA processing. We also showed, similarly to our observations in ACC, that deregulation of TRBP2 expression could affect cell proliferation and cell death in lymphoma cell lines, suggesting its potential oncogenic role in DLBCL development.
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| 3. |
- Christofer Juhlin, C., et al.
(författare)
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Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene
- 2015
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley: 12 months. - 1045-2257 .- 1098-2264. ; 54:9, s. 542-554
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Tidskriftsartikel (refereegranskat)abstract
- As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole-exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis-related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well-established cancer gene lysine (K)-specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome-sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D-mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development. (c) 2015 The Authors. Genes, Chromosomes and Cancer Published by Wiley Periodicals, Inc.
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| 4. |
- Fotouhi, Omid, et al.
(författare)
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Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors
- 2019
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Ingår i: Oncogene. - : NATURE PUBLISHING GROUP. - 0950-9232 .- 1476-5594. ; 38:43, s. 6881-6897
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Tidskriftsartikel (refereegranskat)abstract
- Patients with small intestinal neuroendocrine tumors (SI-NETs) frequently develop spread disease; however, the underlying molecular mechanisms of disease progression are not known and effective preventive treatment strategies are lacking. Here, protein expression profiling was performed by HiRIEF-LC-MS in 14 primary SI-NETs from patients with and without liver metastases detected at the time of surgery and initial treatment. Among differentially expressed proteins, overexpression of the ubiquitin-like protein NEDD8 was identified in samples from patients with liver metastasis. Further, NEDD8 correlation analysis indicated co-expression with RBX1, a key component in cullin-RING ubiquitin ligases (CRLs). In vitro inhibition of neddylation with the therapeutic agent pevonedistat (MLN4924) resulted in a dramatic decrease of proliferation in SI-NET cell lines. Subsequent mass spectrometry-based proteomics analysis of pevonedistat effects and effects of the proteasome inhibitor bortezomib revealed stabilization of multiple targets of CRLs including p27, an established tumor suppressor in SI-NET. Silencing of NEDD8 and RBX1 using siRNA resulted in a stabilization of p27, suggesting that the cellular levels of NEDD8 and RBX1 affect CRL activity. Inhibition of CRL activity, by either NEDD8/RBX1 silencing or pevonedistat treatment of cells resulted in induction of apoptosis that could be partially rescued by siRNA-based silencing of p27. Differential expression of both p27 and NEDD8 was confirmed in a second cohort of SI-NET using immunohistochemistry. Collectively, these findings suggest a role for CRLs and the ubiquitin proteasome system in suppression of p27 in SI-NET, and inhibition of neddylation as a putative therapeutic strategy in SI-NET.
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| 5. |
- Åkerström, Tobias, et al.
(författare)
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Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter.
- 2012
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 7:7
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Tidskriftsartikel (refereegranskat)abstract
- Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na(+) conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.
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