| 1. |
- Alaei-Mahabadi, Babak, et al.
(författare)
-
Global analysis of somatic structural genomic alterations and their impact on gene expression in diverse human cancers.
- 2016
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 113:48, s. 13768-13773
-
Tidskriftsartikel (refereegranskat)abstract
- Tumor genomes are mosaics of somatic structural variants (SVs) that may contribute to the activation of oncogenes or inactivation of tumor suppressors, for example, by altering gene copy number amplitude. However, there are multiple other ways in which SVs can modulate transcription, but the general impact of such events on tumor transcriptional output has not been systematically determined. Here we use whole-genome sequencing data to map SVs across 600 tumors and 18 cancers, and investigate the relationship between SVs, copy number alterations (CNAs), and mRNA expression. We find that 34% of CNA breakpoints can be clarified structurally and that most amplifications are due to tandem duplications. We observe frequent swapping of strong and weak promoters in the context of gene fusions, and find that this has a measurable global impact on mRNA levels. Interestingly, several long noncoding RNAs were strongly activated by this mechanism. Additionally, SVs were confirmed in telomere reverse transcriptase (TERT) upstream regions in several cancers, associated with elevated TERT mRNA levels. We also highlight high-confidence gene fusions supported by both genomic and transcriptomic evidence, including a previously undescribed paired box 8 (PAX8)-nuclear factor, erythroid 2 like 2 (NFE2L2) fusion in thyroid carcinoma. In summary, we combine SV, CNA, and expression data to provide insights into the structural basis of CNAs as well as the impact of SVs on gene expression in tumors.
|
|
| 2. |
- Bhadury, Joydeep, et al.
(författare)
-
BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma
- 2014
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 111:26
-
Tidskriftsartikel (refereegranskat)abstract
- The bromodomain and extraterminal (BET) domain family of proteins binds to acetylated lysines on histones and regulates gene transcription. Recently, BET inhibitors (BETi) have been developed that show promise as potent anticancer drugs against various solid and hematological malignancies. Here we show that the structurally novel and orally bioavailable BET inhibitor RVX2135 inhibits proliferation and induces apoptosis of lymphoma cells arising in Myc-transgenic mice in vitro and in vivo. We find that BET inhibition exhibits broad transcriptional effects in Myc-transgenic lymphoma cells affecting many transcription factor networks. By examining the genes induced by BETi, which have largely been ignored to date, we discovered that these were similar to those induced by histone deacetylase inhibitors (HDACi). HDACi also induced cell-cycle arrest and cell death of Myc-induced murine lymphoma cells and synergized with BETi. Our data suggest that BETi sensitize Myc-overexpressing lymphoma cells partly by inducing HDAC-silenced genes, and suggest synergistic and therapeutic combinations by targeting the genetic link between BETi and HDACi.
|
|
| 3. |
- Bhadury, Joydeep, et al.
(författare)
-
Hypoxia-regulated gene expression explains differences between melanoma cell line-derived xenografts and patient-derived xenografts.
- 2016
-
Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:17
-
Tidskriftsartikel (refereegranskat)abstract
- Cell line-derived xenografts (CDXs) are an integral part of drug efficacy testing during development of new pharmaceuticals against cancer but their accuracy in predicting clinical responses in patients have been debated. Patient-derived xenografts (PDXs) are thought to be more useful for predictive biomarker identification for targeted therapies, including in metastatic melanoma, due to their similarities to human disease. Here, tumor biopsies from fifteen patients and ten widely-used melanoma cell lines were transplanted into immunocompromised mice to generate PDXs and CDXs, respectively. Gene expression profiles generated from the tumors of these PDXs and CDXs clustered into distinct groups, despite similar mutational signatures. Hypoxia-induced gene signatures and overexpression of the hypoxia-regulated miRNA hsa-miR-210 characterized CDXs. Inhibition of hsa-miR-210 with decoys had little phenotypic effect in vitro but reduced sensitivity to MEK1/2 inhibition in vivo, suggesting down-regulation of this miRNA could result in development of resistance to MEK inhibitors.
|
|
| 4. |
- Bhadury, Joydeep, et al.
(författare)
-
Identification of tumorigenic and therapeutically actionable mutations in transplantable mouse tumor cells by exome sequencing.
- 2013
-
Ingår i: Oncogenesis. - : Springer Science and Business Media LLC. - 2157-9024. ; 2
-
Tidskriftsartikel (refereegranskat)abstract
- Cancer development occurs in response to the successive accumulation of mutations that eventually targets key regulators of cell proliferation. As most mutations likely occur randomly, cancer driver mutations can only be found if they are recurrent. Here we use exome sequencing of the mouse cell lines Panc02, L1210 and Colon 26 to identify genetic alterations (single-nucleotide polymorphisms and small insertion and deletions) that occurred in three different strains of mice and that resulted in tumorigenesis. We identify known mutations in genes like Kras, Cdkn2a/b, Smad4 and Trp53 and a large list of genes whose causal link to cancer is unknown. Interestingly, by screening a compound library we find that the identified oncogenic Kras mutation in Colon 26 cells correlates with its sensitivity to MEK inhibitors in vitro and in vivo. Our analysis of these mouse tumor exomes show that their manageable number of mutations could facilitate the identification of novel mutations or pathways driving tumor development. Furthermore, their use as tools is now enhanced as they can be used to create syngenic transplant models for utilization in drug discovery and validation. Finally, by showing that Kras mutant Colon 26 cells are sensitive to MEK inhibitors, we provide one proof-of-principle experiment that a platform containing targeted resequencing and drug screens could be a valuable addition in the clinic to devise anti-cancer drug schemes.
|
|
| 5. |
- Bhadury, Joydeep
(författare)
-
Using genetics to identify epigenetic and signal transduction targets in cancer
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer arises mostly due to the stepwise acquisition of untamed growth capabilities by various means, ranging from genetic, epigenetic to environmental factors. With the advancement made in molecular biology and associated fields, the complex biological circuits leading to these pathological conditions have now started to be deciphered in-depth. In the present thesis I have shown that mouse exome sequencing may be used to guide targeted therapy in animal models (Paper I). In this study, we for the first time made makeshift genomes of two very popular mouse strains namely BALB/c and DBA/2J. In a subsequent paper, we could translate the concept of genetics and mouse modeling for guiding patient enrollment into future clinical trials (Paper II). Thereafter, we used RNA sequencing to decipher similarities shared between cell line-derived xenografts (CDXs) and patient-derived xenografts (PDXs) developed in Paper II. Despite similar mutational profiles, CDXs and PDXs were very different irrespective of their genotype. Here, we unravel hypoxia and specifically hsa-miR-210 as a key player orchestrating the differences (paper III). To our dismay, abrogating the regulation dictated by miR-210 using a miR decoy; makes this cells become less sensitive to MEK inhibition in vivo, suggesting a possible role of hsa-miRNA-210 in conferring resistance to MEK inhibitors. Myc proto-oncogene is deregulated in vast majority of cancers types but unfortunately remains to be inhibited by pharmacological means to date. Recently, Bromodomain and extra-terminal (BET) protein inhibitors (like JQ1) have been shown as an indirect means to inhibit Myc. We set out to test the new and orally bio-available BET inhibitor (RVX2135) in a transgenic mouse model λ-MYC Mouse), where pathogenicity of the disease may be solely attributed to the over-expression of MYC. To our surprise, the data suggested an effect of BET inhibition independent of Myc inhibition using either the prototype JQ1 or the novel compound in our systems (Paper IV). Moreover, we not only show a possible mechanistic insight of BETi but also unravel a synergistic combination of BET and HDAC inhibitors. In a follow up paper, we show lethal synergistic combinations of BET inhibitors and inhibitors of the replication stress kinase ATR in lymphomas (Paper V). Taken together, this thesis unravels the use of various genetic and epigenetic targets as suitable candidates for therapeutical intervention either as standalone and/or in combination; deciphered using different methods as an effective strategy for combating various cancer types both in vitro and in vivo.
|
|
| 6. |
- Einarsdottir, Berglind Osk, 1979, et al.
(författare)
-
Melanoma patient-derived xenografts accurately model the disease and develop fast enough to guide treatment decisions.
- 2014
-
Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 5:20, s. 9609-18
-
Tidskriftsartikel (refereegranskat)abstract
- The development of novel therapies against melanoma would benefit from individualized tumor models to ensure the rapid and accurate identification of biomarkers of therapy response. Previous studies have suggested that patient-derived xenografts (PDXes) could be useful. However, the utility of PDXes in guiding real-time treatment decisions has only been reported in anecdotal forms. Here tumor biopsies from patients with stage III and IV metastatic malignant melanoma were transplanted into immunocompromised mice to generate PDXes. 23/26 melanoma biopsies generated serially transplantable PDX models, and their histology, mutation status and expression profile resembled their corresponding patient biopsy. The potential treatment for one patient was revealed by an in vitro drug screen and treating PDXes with the MEK inhibitor trametinib. In another patient, the BRAF mutation predicted the response of both the patient and its corresponding PDXes to MAPK-targeted therapy. Importantly, in this unselected group of patients, the time from biopsy for generation of PDXes until death was significantly longer than the time required to reach the treatment phase of the PDXes. Thus, it could be clinically meaningful to use this type of platform for melanoma patients as a pre-selection tool in clinical trials.
|
|
| 7. |
|
|
| 8. |
- Muralidharan, Somsundar Veppil, et al.
(författare)
-
BET bromodomain inhibitors synergize with ATR inhibitors in melanoma in melanoma.
- 2017
-
Ingår i: Cell Death & Disease. - 2041-4889. ; 8:8, s. 1-7
-
Tidskriftsartikel (refereegranskat)abstract
- Metastatic malignant melanoma continues to be a challenging disease despite clinical translation of the comprehensive understanding of driver mutations and how melanoma cells evade immune attack. In Myc-driven lymphoma, efficacy of epigenetic inhibitors of the bromodomain and extra-terminal domain (BET) family of bromodomain proteins can be enhanced by combination therapy with inhibitors of the DNA damage response kinase ATR. Whether this combination is active in solid malignancies like melanoma, and how it relates to immune therapy, has not previously investigated. To test efficacy and molecular consequences of combination therapies cultured melanoma cells were used. To assess tumor responses to therapies in vivo we use patient-derived xenografts and B6 mice transplanted with B16F10 melanoma cells. Concomitant inhibition of BET proteins and ATR of cultured melanoma cells resulted in similar effects as recently shown in lymphoma, such as induction of apoptosis and p62, implicated in autophagy, senescence-associated secretory pathway and ER stress. In vivo, apoptosis and suppression of subcutaneous growth of patient-derived melanoma and B16F10 cells were observed. Our data suggest that ATRI/BETI combination therapies are effective in melanoma.
|
|
| 9. |
- Muralidharan, Somsundar Veppil, et al.
(författare)
-
BET bromodomain inhibitors synergize with ATR inhibitors to induce DNA damage, apoptosis, senescence-associated secretory pathway and ER stress in Myc-induced lymphoma cells.
- 2016
-
Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 35, s. 4689-4697
-
Tidskriftsartikel (refereegranskat)abstract
- Inhibiting the bromodomain and extra-terminal (BET) domain family of epigenetic reader proteins has been shown to have potent anti-tumoral activity, which is commonly attributed to suppression of transcription. In this study, we show that two structurally distinct BET inhibitors (BETi) interfere with replication and cell cycle progression of murine Myc-induced lymphoma cells at sub-lethal concentrations when the transcriptome remains largely unaltered. This inhibition of replication coincides with a DNA-damage response and enhanced sensitivity to inhibitors of the upstream replication stress sensor ATR in vitro and in mouse models of B-cell lymphoma. Mechanistically, ATR and BETi combination therapy cause robust transcriptional changes of genes involved in cell death, senescence-associated secretory pathway, NFkB signaling and ER stress. Our data reveal that BETi can potentiate the cell stress and death caused by ATR inhibitors. This suggests that ATRi can be used in combination therapies of lymphomas without the use of genotoxic drugs.Oncogene advance online publication, 25 January 2016; doi:10.1038/onc.2015.521.
|
|
| 10. |
- Nilsson, Lisa M, 1976, et al.
(författare)
-
Cancer Differentiating Agent Hexamethylene Bisacetamide Inhibits BET Bromodomain Proteins
- 2016
-
Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 76:8, s. 2376-2383
-
Tidskriftsartikel (refereegranskat)abstract
- Agents that trigger cell differentiation are highly efficacious in treating certain cancers, but such approaches are not generally effective in most malignancies. Compounds such as DMSO and hexamethylene bisacetamide (HMBA) have been used to induce differentiation in experimental systems, but their mechanisms of action and potential range of uses on that basis have not been developed. Here, we show that HMBA, a compound first tested in the oncology clinic over 25 years ago, acts as a selective bromodomain inhibitor. Biochemical and structural studies revealed an affinity of HMBA for the second bromodomain of BET proteins. Accordingly, both HMBA and the prototype BET inhibitor JQ1 induced differentiation of mouse erythroleukemia cells. As expected of a BET inhibitor, HMBA displaced BET proteins from chromatin, caused massive transcriptional changes, and triggered cell-cycle arrest and apoptosis in Myc-induced B-cell lymphoma cells. Furthermore, HMBA exerted anticancer effects in vivo in mouse models of Myc-driven B-cell lymphoma. This study illuminates the function of an early anticancer agent and suggests an intersection with ongoing clinical trials of BET inhibitor, with several implications for predicting patient selection and response rates to this therapy and starting points for generating BD2-selective BET inhibitors. (C) 2016 AACR.
|
|
