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  • 1. Bruzzese, Francesca
    et al.
    Hagglof, Christina
    Leone, Alessandra
    Sjoberg, Elin
    Roca, Maria Serena
    Kiflemariam, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Hammarsten, Peter
    Egevad, Lars
    Bergh, Anders
    Ostman, Arne
    Budillon, Alfredo
    Augsten, Martin
    Local and Systemic Protumorigenic Effects of Cancer-Associated Fibroblast-Derived GDF152014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 13, p. 3408-3417Article in journal (Refereed)
    Abstract [en]

    The tumor stroma is vital to tumor development, progression, and metastasis. Cancer-associated fibroblasts (CAF) are among the abundant cell types in the tumor stroma, but the range of their contributions to cancer pathogenicity has yet to be fully understood. Here, we report a critical role for upregulation of the TGF beta/BMP family member GDF15 (MIC-1) in tumor stroma. GDF15 was found upregulated in situ and in primary cultures of CAF from prostate cancer. Ectopic expression of GDF15 in fibroblasts produced prominent paracrine effects on prostate cancer cell migration, invasion, and tumor growth. Notably, GDF15-expressing fibroblasts exerted systemic in vivo effects on the outgrowth of distant and otherwise indolent prostate cancer cells. Our findings identify tumor stromal cells as a novel source of GDF15 in human prostate cancer and illustrate a systemic mechanism of cancer progression driven by the tumor microenvironment. Further, they provide a functional basis to understand GDF15 as a biomarker of poor prognosis and a candidate therapeutic target in prostate cancer. 

  • 2. Grundberg, Ida
    et al.
    Kiflemariam, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mignardi, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Imgenberg-Kreuz, Juliana
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Edlund, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sundström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nilsson, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    In situ mutation detection and visualization of intratumor heterogeneity for cancer research and diagnostics2013In: Oncotarget, ISSN 1949-2553, Vol. 4, no 12, p. 2407-2418Article in journal (Refereed)
    Abstract [en]

    Current assays for somatic mutation analysis are based on extracts from tissue sections that often contain morphologically heterogeneous neoplastic regions with variable contents of normal stromal and inflammatory cells, obscuring the results of the assays. We have developed an RNA-based in situ mutation assay that targets oncogenic mutations in a multiplex fashion that resolves the heterogeneity of the tissue sample. Activating oncogenic mutations are targets for a new generation of cancer drugs. For anti-EGFR therapy prediction, we demonstrate reliable in situ detection of KRAS mutations in codon 12 and 13 in colon and lung cancers in three different types of routinely processed tissue materials. High-throughput screening of KRAS mutation status was successfully performed on a tissue microarray. Moreover, we show how the patterns of expressed mutated and wild-type alleles can be studied in situ in tumors with complex combinations of mutated EGFR, KRAS and TP53. This in situ method holds great promise as a tool to investigate the role of somatic mutations during tumor progression and for prediction of response to targeted therapy.

  • 3.
    Kiflemariam, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Expression and Mutation Analyses of Candidate Cancer Genes In Situ2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cancers display heterogeneity in genetic profiles of the individual cancer cells and in the composition of different malignant and non-malignant cell populations. Such intra-tumor heterogeneity plays a role in treatment response and the emergence of resistance to cancer therapies. Approaches that address this complexity and improve stratification of patients for treatment are therefore highly warranted. Thus, the aims of this thesis were to further develop and apply in situ technologies for expression and mutation analyses of candidate cancer genes to gain a deeper understanding of cancer biology and to study intra-tumor heterogeneity.

    In paper I, we established and validated a procedure for scalable in situ hybridization of large gene sets in human formalin-fixed paraffin-embedded tissues for analysis of gene expression. This method was used in paper II for large-scale expression analysis of the tyrosine kinome and phosphatome, two gene families whose members are frequently mutated in many forms of cancers. Systematic, compartment-specific expression mapping at cell type resolution enabled us to identify several novel vascular markers that have gone unnoticed in bulk transcriptomic analyses. In papers III and IV, we used padlock probes for in situ mutation detection in single cells for studies of genetic intra-tumor heterogeneity. In paper III, multiplex detection and genotyping of oncogenic point mutations was demonstrated in routinely processed tissue materials, whereas in paper IV we further the application by demonstrating multiplex detection of fusion gene transcripts.

    Collectively, the work presented in this thesis employs in situ-based methods to obtain spatial resolution of gene expression and mutation patterns in normal and cancer tissues, thereby broadening our understanding of the cancer genome.

    List of papers
    1. Scalable In Situ Hybridization on Tissue Arrays for Validation of Novel Cancer and Tissue-Specific Biomarkers
    Open this publication in new window or tab >>Scalable In Situ Hybridization on Tissue Arrays for Validation of Novel Cancer and Tissue-Specific Biomarkers
    Show others...
    2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3, p. e32927-Article in journal (Refereed) Published
    Abstract [en]

    Tissue localization of gene expression is increasingly important for accurate interpretation of large scale datasets from expression and mutational analyses. To this end, we have (1) developed a robust and scalable procedure for generation of mRNA hybridization probes, providing >95% first-pass success rate in probe generation to any human target gene and (2) adopted an automated staining procedure for analyses of formalin-fixed paraffin-embedded tissues and tissue microarrays. The in situ mRNA and protein expression patterns for genes with known as well as unknown tissue expression patterns were analyzed in normal and malignant tissues to assess procedure specificity and whether in situ hybridization can be used for validating novel antibodies. We demonstrate concordance between in situ transcript and protein expression patterns of the well-known pathology biomarkers KRT17, CHGA, MKI67, PECAM1 and VIL1, and provide independent validation for novel antibodies to the biomarkers BRD1, EZH2, JUP and SATB2. The present study provides a foundation for comprehensive in situ gene set or transcriptome analyses of human normal and tumor tissues.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-174583 (URN)10.1371/journal.pone.0032927 (DOI)000303062000022 ()
    Available from: 2012-05-29 Created: 2012-05-22 Last updated: 2017-12-07Bibliographically approved
    2. Expression analysis at cell type resolution of the tyrosine kinome and phosphatome in human normal and malignant tissues
    Open this publication in new window or tab >>Expression analysis at cell type resolution of the tyrosine kinome and phosphatome in human normal and malignant tissues
    (English)Manuscript (preprint) (Other academic)
    National Category
    Genetics Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:uu:diva-184501 (URN)
    Available from: 2012-11-07 Created: 2012-11-07 Last updated: 2013-02-11
    3. In situ mutation detection in cancer tissue sections for research and diagnostics in clinical oncology
    Open this publication in new window or tab >>In situ mutation detection in cancer tissue sections for research and diagnostics in clinical oncology
    Show others...
    (English)Article in journal (Other academic) Submitted
    National Category
    Genetics Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:uu:diva-184506 (URN)
    Available from: 2012-11-07 Created: 2012-11-07 Last updated: 2013-02-11
    4. Direct detection of TMPRSS2-ERG fusion transcripts in prostate cancer tissues by padlock probes
    Open this publication in new window or tab >>Direct detection of TMPRSS2-ERG fusion transcripts in prostate cancer tissues by padlock probes
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Genetics Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:uu:diva-184507 (URN)
    Available from: 2012-11-07 Created: 2012-11-07 Last updated: 2013-02-11
  • 4.
    Kiflemariam, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Sandra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Scalable In Situ Hybridization on Tissue Arrays for Validation of Novel Cancer and Tissue-Specific Biomarkers2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3, p. e32927-Article in journal (Refereed)
    Abstract [en]

    Tissue localization of gene expression is increasingly important for accurate interpretation of large scale datasets from expression and mutational analyses. To this end, we have (1) developed a robust and scalable procedure for generation of mRNA hybridization probes, providing >95% first-pass success rate in probe generation to any human target gene and (2) adopted an automated staining procedure for analyses of formalin-fixed paraffin-embedded tissues and tissue microarrays. The in situ mRNA and protein expression patterns for genes with known as well as unknown tissue expression patterns were analyzed in normal and malignant tissues to assess procedure specificity and whether in situ hybridization can be used for validating novel antibodies. We demonstrate concordance between in situ transcript and protein expression patterns of the well-known pathology biomarkers KRT17, CHGA, MKI67, PECAM1 and VIL1, and provide independent validation for novel antibodies to the biomarkers BRD1, EZH2, JUP and SATB2. The present study provides a foundation for comprehensive in situ gene set or transcriptome analyses of human normal and tumor tissues.

  • 5.
    Kiflemariam, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Mignardi, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Bergh, A.
    Nilsson, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sjoblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Direct Detection of TMPRSS2-ERG Rearrangements in Prostate Cancer by Padlock Probes2012In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 48, no S5, p. S110-S110Article in journal (Refereed)
  • 6.
    Kiflemariam, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mignardi, Marco
    Ali, Muhammad Akhtar
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Bergh, Anders
    Nilsson, Mats
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    In situ sequencing identifies TMPRSS2-ERG fusion transcripts, somatic point mutations and gene expression levels in prostate cancers2014In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 234, no 2, p. 253-261Article in journal (Refereed)
    Abstract [en]

    Translocations contribute to the genesis and progression of epithelial tumours and in particular to prostate cancerdevelopment. To better understand the contribution of fusion transcripts and visualize the clonal composition ofmultifocal tumours, we have developed a technology for multiplexin situdetection and identification of expressedfusion transcripts. When compared to immunohistochemistry,TMPRSS2–ERGfusion-negative and fusion-positiveprostate tumours were correctly classified. The most prevalentTMPRSS2–ERGfusion variants were visualized,identified, and quantitated in human prostate cancer tissues, and the ratio of the variant fusion transcripts couldfor the first time be directly determined byin situsequencing. Further, we demonstrate concurrentin situdetectionof gene expression, point mutations, and gene fusions of the prostate cancer relevant targetsAMACR,AR,TP53,andTMPRSS2–ERG. This unified approach toin situanalyses of somatic mutations can empower studies ofintra-tumoural heterogeneity and future tissue-based diagnostics of mutations and translocations.

  • 7. Pena, Cristina
    et al.
    Virtudes Cespedes, Maria
    Lindh, Maja Bradic
    Kiflemariam, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Mezheyeuski, Artur
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Hagglof, Christina
    Birgisson, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Bojmar, Linda
    Jirstrom, Karin
    Sandstrom, Per
    Olsson, Eleonor
    Veerla, Srinivas
    Gallardo, Alberto
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Chang, Andy C. -M.
    Reddel, Roger R.
    Mangues, Ramon
    Augsten, Martin
    Ostman, Arne
    STC1 Expression By Cancer-Associated Fibroblasts Drives Metastasis of Colorectal Cancer2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 4, p. 1287-1297Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant of cancer-associated fibroblasts (CAF). Elevated expression of PDGF receptors on stromal CAFs is associated with metastasis and poor prognosis, but mechanism(s) that underlie these connections are not understood. Here, we report the identification of the secreted glycoprotein stanniocalcin-1 (STC1) as a mediator of metastasis by PDGF receptor function in the setting of colorectal cancer. PDGF-stimulated fibroblasts increased migration and invasion of cocultured colorectal cancer cells in an STC1-dependent manner. Analyses of human colorectal cancers revealed significant associations between stromal PDGF receptor and STC1 expression. In an orthotopic mouse model of colorectal cancer, tumors formed in the presence of STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. Our results reveal a mechanistic basis for understanding the contribution of PDGF-activated CAFs to cancer metastasis.

  • 8.
    Weibrecht, Irene
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundin, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kiflemariam, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mignardi, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grundberg, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Chatarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Koos, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    In situ detection of individual mRNA molecules and protein complexes or post-translational modifications using padlock probes combined with the in situ proximity ligation assay2013In: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 8, no 2, p. 355-372Article in journal (Refereed)
    Abstract [en]

    Analysis at the single-cell level is essential for the understanding of cellular responses in heterogeneous cell populations, but it has been difficult to perform because of the strict requirements put on detection methods with regard to selectivity and sensitivity (i.e., owing to the cross-reactivity of probes and limited signal amplification). Here we describe a 1.5-d protocol for enumerating and genotyping mRNA molecules in situ while simultaneously obtaining information on protein interactions or post-translational modifications; this is achieved by combining padlock probes with in situ proximity ligation assays (in situ PLA). In addition, we provide an example of how to design padlock probes and how to optimize staining conditions for fixed cells and tissue sections. Both padlock probes and in situ PLA provide the ability to directly visualize single molecules by standard microscopy in fixed cells or tissue sections, and these methods may thus be valuable for both research and diagnostic purposes.

1 - 8 of 8
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