uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Sjöblom, Tobias
Alternative names
Publications (10 of 42) Show all publications
Uhlen, M., Zhang, C., Lee, S., Sjöstedt, E., Fagerberg, L., Bidkhori, G., . . . Ponten, F. (2017). A pathology atlas of the human cancer transcriptome. Science, 357(6352), Article ID eaan2507.
Open this publication in new window or tab >>A pathology atlas of the human cancer transcriptome
Show others...
2017 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 357, no 6352, eaan2507Article in journal (Refereed) Published
Abstract [en]

Cancer is one of the leading causes of death, and there is great interest in understanding the underlying molecular mechanisms involved in the pathogenesis and progression of individual tumors. We used systems-level approaches to analyze the genome-wide transcriptome of the protein-coding genes of 17 major cancer types with respect to clinical outcome. A general pattern emerged: Shorter patient survival was associated with up-regulation of genes involved in cell growth and with down-regulation of genes involved in cellular differentiation. Using genome-scale metabolic models, we show that cancer patients have widespread metabolic heterogeneity, highlighting the need for precise and personalized medicine for cancer treatment. All data are presented in an interactive open-access database (www.proteinatlas.org/pathology) to allow genome-wide exploration of the impact of individual proteins on clinical outcomes.

Place, publisher, year, edition, pages
AMER ASSOC ADVANCEMENT SCIENCE, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-334302 (URN)10.1126/science.aan2507 (DOI)000407793600028 ()
Funder
Swedish Cancer SocietyScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceKnut and Alice Wallenberg FoundationSwedish Research Council
Available from: 2017-11-22 Created: 2017-11-22 Last updated: 2017-11-22Bibliographically approved
Larsson, C., Ali, M. A., Djureinovic, T., Lindroth, A. M., He, L. & Sjöblom, T. (2017). Loss of DIP2C in RKO cells stimulates changes in DNA methylation and epithelial-mesenchymal transition. BMC Cancer, 17, Article ID 487.
Open this publication in new window or tab >>Loss of DIP2C in RKO cells stimulates changes in DNA methylation and epithelial-mesenchymal transition
Show others...
2017 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 17, 487Article in journal (Refereed) Published
Abstract [en]

Background: The disco-interacting protein 2 homolog C (DIP2C) gene is an uncharacterized gene found mutated in a subset of breast and lung cancers. To understand the role of DIP2C in tumour development we studied the gene in human cancer cells.

Methods: We engineered human DIP2C knockout cells by genome editing in cancer cells. The growth properties of the engineered cells were characterised and transcriptome and methylation analyses were carried out to identify pathways deregulated by inactivation of DIP2C. Effects on cell death pathways and epithelial-mesenchymal transition traits were studied based on the results from expression profiling.

Results: Knockout of DIP2C in RKO cells resulted in cell enlargement and growth retardation. Expression profiling revealed 780 genes for which the expression level was affected by the loss of DIP2C, including the tumour-suppressor encoding CDKN2A gene, the epithelial-mesenchymal transition (EMT) regulator-encoding ZEB1, and CD44 and CD24 that encode breast cancer stem cell markers. Analysis of DNA methylation showed more than 30,000 sites affected by differential methylation, the majority of which were hypomethylated following loss of DIP2C. Changes in DNA methylation at promoter regions were strongly correlated to changes in gene expression, and genes involved with EMT and cell death were enriched among the differentially regulated genes. The DIP2C knockout cells had higher wound closing capacity and showed an increase in the proportion of cells positive for cellular senescence markers.

Conclusions: Loss of DIP2C triggers substantial DNA methylation and gene expression changes, cellular senescence and epithelial-mesenchymal transition in cancer cells.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD, 2017
Keyword
Cancer, DIP2C, Gene knockout, rAAV-mediated gene targeting, Tumour cell biology, DNA methylation, Epithelial-mesenchymal transition (EMT)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-331232 (URN)10.1186/s12885-017-3472-5 (DOI)000405865300001 ()28716088 (PubMedID)
Funder
Swedish Cancer Society, 2006/2154, 2007/775, 2012/834, 2012/1235Swedish Foundation for Strategic Research , F06-0050, RBa08-0114Swedish Society for Medical Research (SSMF)
Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2017-11-29Bibliographically approved
Karlsson, H., Fryknäs, M., Strese, S., Gullbo, J., Westman, G., Bremberg, U., . . . Nygren, P. (2017). Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity. OncoTarget, 8(18), 30217-30234.
Open this publication in new window or tab >>Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
Show others...
2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 18, 30217-30234 p.Article in journal (Refereed) Published
Abstract [en]

Background: The thiosemicarbazone CD 02750 (VLX50) was recently reported as a hit compound in a phenotype-based drug screen in primary cultures of patient tumor cells. We synthesized a copper complex of VLX50, denoted VLX60, and characterized its antitumor and mechanistic properties.

Materials and Methods: The cytotoxic effects and mechanistic properties of VLX60 were investigated in monolayer cultures of multiple human cell lines, in tumor cells from patients, in a 3-D spheroid cell culture system and in vivo and were compared with those of VLX50.

Results: VLX60 showed >= 3-fold higher cytotoxic activity than VLX50 in 2-D cultures and, in contrast to VLX50, retained its activity in the presence of additional iron. VLX60 was effective against non-proliferative spheroids and against tumor xenografts in vivo in a murine model. In contrast to VLX50, gene expression analysis demonstrated that genes associated with oxidative stress were considerably enriched in cells exposed to VLX60 as was induction of reactive oxygen. VLX60 compromised the ubiquitin-proteasome system and was more active in BRAF mutated versus BRAF wild-type colon cancer cells.

Conclusions: The cytotoxic effects of the copper thiosemicarbazone VLX60 differ from those of VLX50 and shows interesting features as a potential antitumor drug, notably against BRAF mutated colorectal cancer.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keyword
cancer drug, thiosemicarbazone, spheroid, VLX60, BRAF
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-323035 (URN)10.18632/oncotarget.16324 (DOI)000400456200055 ()28415818 (PubMedID)
Funder
Swedish Cancer SocietySwedish Foundation for Strategic Research
Available from: 2017-06-01 Created: 2017-06-01 Last updated: 2017-11-29Bibliographically approved
Kühnemund, M., Wei, Q., Darai, E., Wang, Y., Hernandez-Neuta, I., Yang, Z., . . . Nilsson, M. (2017). Targeted DNA sequencing and in situ mutation analysis using mobile phone microscopy. Nature Communications, 8, Article ID 13913.
Open this publication in new window or tab >>Targeted DNA sequencing and in situ mutation analysis using mobile phone microscopy
Show others...
2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, 13913Article in journal (Refereed) Published
Abstract [en]

Molecular diagnostics is typically outsourced to well-equipped centralized laboratories, often far from the patient. We developed molecular assays and portable optical imaging designs that permit on-site diagnostics with a cost-effective mobile-phone-based multimodal microscope. We demonstrate that targeted next-generation DNA sequencing reactions and in situ point mutation detection assays in preserved tumour samples can be imaged and analysed using mobile phone microscopy, achieving a new milestone for tele-medicine technologies.

National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:uu:diva-315810 (URN)10.1038/ncomms13913 (DOI)000391931300001 ()28094784 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer Society, 2015/838 2015/629Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2017-02-22 Created: 2017-02-22 Last updated: 2017-11-29Bibliographically approved
Pandzic, T., Larsson, J., He, L., Kundu, S., Ban, K., Ali, M. A., . . . Hellström, M. (2016). Transposon Mutagenesis Reveals Fludarabine Resistance Mechanisms in Chronic Lymphocytic Leukemia. Clinical Cancer Research, 22(24), 6217-6227.
Open this publication in new window or tab >>Transposon Mutagenesis Reveals Fludarabine Resistance Mechanisms in Chronic Lymphocytic Leukemia
Show others...
2016 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 24, 6217-6227 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: To identify resistance mechanisms for the chemotherapeutic drug fludarabine in chronic lymphocytic leukemia (CLL), as innate and acquired resistance to fludarabine-based chemotherapy represents a major challenge for long-term disease control. Experimental Design: We used piggyBac transposon-mediated mutagenesis, combined with next-generation sequencing, to identify genes that confer resistance to fludarabine in a human CLL cell line. Results: In total, this screen identified 782 genes with transposon integrations in fludarabine-resistant pools of cells. One of the identified genes is a known resistance mediator DCK (deoxycytidine kinase), which encodes an enzyme that is essential for the phosphorylation of the prodrug to the active metabolite. BMP2K, a gene not previously linked to CLL, was also identified as a modulator of response to fludarabine. In addition, 10 of 782 transposon-targeted genes had previously been implicated in treatment resistance based on somatic mutations seen in patients refractory to fludarabine-based therapy. Functional characterization of these genes supported a significant role for ARID5B and BRAF in fludarabine sensitivity. Finally, pathway analysis of transposon-targeted genes and RNA-seq profiling of fludarabine-resistant cells suggested deregulated MAPK signaling as involved in mediating drug resistance in CLL. Conclusions: To our knowledge, this is the first forward genetic screen for chemotherapy resistance in CLL. The screen pinpointed novel genes and pathways involved in fludarabine resistance along with previously known resistance mechanisms. Transposon screens can therefore aid interpretation of cancer genome sequencing data in the identification of genes modifying sensitivity to chemotherapy.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-315914 (URN)10.1158/1078-0432.CCR-15-2903 (DOI)000391472400028 ()26957556 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilSwedish National Infrastructure for Computing (SNIC), b2014071
Available from: 2017-02-23 Created: 2017-02-23 Last updated: 2017-11-29Bibliographically approved
Ljungström, V., Cortese, D., Young, E., Pandzic, T., Mansouri, L., Plevova, K., . . . Rosenquist, R. (2016). Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations. Blood, 127(8), 1007-1016.
Open this publication in new window or tab >>Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations
Show others...
2016 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 127, no 8, 1007-1016 p.Article in journal (Refereed) Published
Abstract [en]

Fludarabine, cyclophosphamide and rituximab (FCR) is first-line treatment for medically fit chronic lymphocytic leukemia (CLL) patients, however despite good response rates many patients eventually relapse. Whilst recent high-throughput studies have identified novel recurrent genetic lesions in adverse-prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, BIRC3) a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal prior to treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared to wildtype RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-257013 (URN)10.1182/blood-2015-10-674572 (DOI)000373397800011 ()26675346 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilEU, European Research CouncilSwedish National Infrastructure for Computing (SNIC)
Note

De två första författarna delar förstaförfattarskapet.

De två sista författarna delar sistaförfattarskapet.

Available from: 2015-06-29 Created: 2015-06-29 Last updated: 2018-01-11Bibliographically approved
Stoimenov, I., Ali, M. A., Pandzic, T. & Sjöblom, T. (2015). Computational and molecular tools for scalable rAAV-mediated genome editing. Nucleic Acids Research, 43(5), Article ID e30.
Open this publication in new window or tab >>Computational and molecular tools for scalable rAAV-mediated genome editing
2015 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 43, no 5, e30Article in journal (Refereed) Published
Abstract [en]

The rapid discovery of potential driver mutations through large-scale mutational analyses of human cancers generates a need to characterize their cellular phenotypes. Among the techniques for genome editing, recombinant adeno-associated virus (rAAV)-mediated gene targeting is suited for knock-in of single nucleotide substitutions and to a lesser degree for gene knock-outs. However, the generation of gene targeting constructs and the targeting process is time-consuming and labor-intense. To facilitate rAAV-mediated gene targeting, we developed the first software and complementary automation-friendly vector tools to generate optimized targeting constructs for editing human protein encoding genes. By computational approaches, rAAV constructs for editing similar to 71% of bases in protein-coding exons were designed. Similarly, similar to 81% of genes were predicted to be targetable by rAAV-mediated knock-out. A Gateway-based cloning system for facile generation of rAAV constructs suitable for robotic automation was developed and used in successful generation of targeting constructs. Together, these tools enable automated rAAV targeting construct design, generation as well as enrichment and expansion of targeted cells with desired integrations.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-252714 (URN)10.1093/nar/gku1286 (DOI)000352487100003 ()25488813 (PubMedID)
Available from: 2015-05-11 Created: 2015-05-11 Last updated: 2017-12-04Bibliographically approved
Ljungström, V., Cortese, D., Young, E., Pandzic, T., Mansouri, L., Plevova, K., . . . Rosenquist, R. (2015). DISSECTING RESISTANCE MECHANISMS IN CHRONIC LYMPHOCYTIC LEUKEMIA USING WHOLE-EXOME SEQUENCING: IMPACT OF RECURRENT RPS15 MUTATIONS ON P53 DYSREGULATION. Paper presented at 20th Congress of European-Hematology-Association, JUN 11-14, 2015, Vienna, AUSTRIA. Haematologica, 100, 10-11.
Open this publication in new window or tab >>DISSECTING RESISTANCE MECHANISMS IN CHRONIC LYMPHOCYTIC LEUKEMIA USING WHOLE-EXOME SEQUENCING: IMPACT OF RECURRENT RPS15 MUTATIONS ON P53 DYSREGULATION
Show others...
2015 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, 10-11 p.Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-266165 (URN)000361204901021 ()
Conference
20th Congress of European-Hematology-Association, JUN 11-14, 2015, Vienna, AUSTRIA
Available from: 2015-11-11 Created: 2015-11-05 Last updated: 2017-12-01Bibliographically approved
Sahin, U., Zitvogel, L., Andre, F., Thielemans, K., De Greve, J., Kundig, T., . . . Lindman, H. (2015). Mutanome Engineered RNA Immunotherapy (MERIT). HUMAN GENE THERAPY CLINICAL DEVELOPMENT, 26(2), 84-86.
Open this publication in new window or tab >>Mutanome Engineered RNA Immunotherapy (MERIT)
Show others...
2015 (English)In: HUMAN GENE THERAPY CLINICAL DEVELOPMENT, ISSN 2324-8637, Vol. 26, no 2, 84-86 p.Article in journal (Refereed) Published
National Category
Medical Genetics Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-265946 (URN)10.1089/humc.2015.2524 (DOI)000362315000006 ()
Funder
EU, European Research Council, 601939
Available from: 2015-11-04 Created: 2015-11-04 Last updated: 2018-01-10Bibliographically approved
Heesch, S., Britten, C. M., Bukur, V., Buck, J., Castle, J., Diekmann, J., . . . Sahin, U. (2015). The Mutanome Engineered RNA Immuno-Therapy (MERIT) project. Paper presented at 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR), APR 18-22, 2015, Philadelphia, PA. Cancer Research, 75.
Open this publication in new window or tab >>The Mutanome Engineered RNA Immuno-Therapy (MERIT) project
Show others...
2015 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-298978 (URN)10.1158/1538-7445.AM2015-CT201 (DOI)000371597100036 ()
Conference
106th Annual Meeting of the American-Association-for-Cancer-Research (AACR), APR 18-22, 2015, Philadelphia, PA
Available from: 2016-07-13 Created: 2016-07-12 Last updated: 2017-11-28Bibliographically approved
Organisations

Search in DiVA

Show all publications