{"entity": "journal", "iuid": "3cf12452f6a9498d8ccdfbf2917e60ce", "timestamp": "2026-03-09T08:29:46.635Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/journal/Mol%20Oncol.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/journal/Mol%20Oncol"}}, "title": "Mol Oncol", "issn": "1878-0261", "issn-l": "1574-7891", "publications_count": 11, "publications": [{"entity": "publication", "iuid": "19c5c3cd794b4250bb2a6ff65d9665f1", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/19c5c3cd794b4250bb2a6ff65d9665f1.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/19c5c3cd794b4250bb2a6ff65d9665f1"}}, "title": "TGF\u03b2 selects for pro-stemness over pro-invasive phenotypes during cancer cell epithelial-mesenchymal transition.", "authors": [{"family": "Tsubakihara", "given": "Yutaro", "initials": "Y"}, {"family": "Ohata", "given": "Yae", "initials": "Y", "orcid": "0000-0002-5518-835X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/97ecb5ad5b6a4aa69a4d84523cb84918.json"}}, {"family": "Okita", "given": "Yukari", "initials": "Y", "orcid": "0000-0002-7279-4634", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/35f1dd6b5aa74ab9a53620c614680674.json"}}, {"family": "Younis", "given": "Shady", "initials": "S", "orcid": "0000-0002-4319-1738", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/cd2c4773dcf84b9eb1b82d19e5e2039c.json"}}, {"family": "Eriksson", "given": "Jens", "initials": "J", "orcid": "0000-0002-8945-2665", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/fe04815d524b48c2ba80c094c629362f.json"}}, {"family": "Sellin", "given": "Mikael E", "initials": "ME", "orcid": "0000-0002-8355-0803", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/559c18ec87d64318a0afc6267ea879e2.json"}}, {"family": "Ren", "given": "Jiang", "initials": "J"}, {"family": "Ten Dijke", "given": "Peter", "initials": "P", "orcid": "0000-0002-7234-342X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/2193ff2b5f924395ac6d4a9ddd53f20e.json"}}, {"family": "Miyazono", "given": "Kohei", "initials": "K", "orcid": "0000-0001-7341-0172", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/88b0a85433264e96a3c4f2e27ca0e3f7.json"}}, {"family": "Hikita", "given": "Atsuhiko", "initials": "A", "orcid": "0000-0001-9552-2976", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d8d3ea8a83164bb7af09a879dfe8c52f.json"}}, {"family": "Imamura", "given": "Takeshi", "initials": "T", "orcid": "0000-0001-5101-4304", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a694d49ba34d4aac8f6b73e21f0303e1.json"}}, {"family": "Kato", "given": "Mitsuyasu", "initials": "M", "orcid": "0000-0001-9905-2473", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/04d3edbf488a445583e31a14d7576aca.json"}}, {"family": "Heldin", "given": "Carl-Henrik", "initials": "CH", "orcid": "0000-0002-9508-896X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5bca6678f5eb4baf853fca6ed5f9b726.json"}}, {"family": "Moustakas", "given": "Aristidis", "initials": "A", "orcid": "0000-0001-9131-3827", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/f11771bffabf4da6a2a5e2668c7c7c2d.json"}}], "type": "journal article", "published": "2022-06-00", "journal": {"title": "Mol Oncol", "issn": "1878-0261", "volume": "16", "issue": "12", "pages": "2330-2354", "issn-l": "1574-7891"}, "abstract": "Transforming growth factor \u03b2 (TGF\u03b2) induces epithelial-mesenchymal transition (EMT), which correlates with stemness and invasiveness. Mesenchymal-epithelial transition (MET) is induced by TGF\u03b2 withdrawal and correlates with metastatic colonization. Whether TGF\u03b2 promotes stemness and invasiveness simultaneously via EMT remains unclear. We established a breast cancer cell model expressing red fluorescent protein (RFP) under the E-cadherin promoter. In 2D cultures, TGF\u03b2 induced EMT, generating RFPlow cells with a mesenchymal transcriptome, and regained RFP, with an epithelial transcriptome, after MET induced by TGF\u03b2 withdrawal. RFPlow cells generated robust mammospheres, with epithelio-mesenchymal cell surface features. Mammospheres that were forced to adhere generated migratory cells, devoid of RFP, a phenotype which was inhibited by a TGF\u03b2 receptor kinase inhibitor. Further stimulation of RFPlow mammospheres with TGF\u03b2 suppressed the generation of motile cells, but enhanced mammosphere growth. Accordingly, mammary fat-pad-transplanted mammospheres, in the absence of exogenous TGF\u03b2 treatment, established lung metastases with evident MET (RFPhigh cells). In contrast, TGF\u03b2-treated mammospheres revealed high tumour-initiating capacity, but limited metastatic potential. Thus, the biological context of partial EMT and MET allows TGF\u03b2 to differentiate between pro-stemness and pro-invasive phenotypes.", "doi": "10.1002/1878-0261.13215", "pmid": "35348275", "labels": {"SciLifeLab Fellow": null, "Mikael Sellin": null}, "xrefs": [{"db": "pmc", "key": "PMC9208077"}, {"db": "RefSeq", "key": "E-MTAB-97509"}], "notes": [], "created": "2022-12-04T11:00:00.977Z", "modified": "2022-12-04T11:00:01.263Z"}, {"entity": "publication", "iuid": "353c589cc2fd49779557600155b35592", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/353c589cc2fd49779557600155b35592.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/353c589cc2fd49779557600155b35592"}}, "title": "Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer.", "authors": [{"family": "Bruun", "given": "Jarle", "initials": "J"}, {"family": "Sveen", "given": "Anita", "initials": "A"}, {"family": "Barros", "given": "Rita", "initials": "R"}, {"family": "Eide", "given": "Peter W", "initials": "PW"}, {"family": "Eilertsen", "given": "Ina", "initials": "I"}, {"family": "Kolberg", "given": "Matthias", "initials": "M"}, {"family": "Pellinen", "given": "Teijo", "initials": "T"}, {"family": "David", "given": "Leonor", "initials": "L"}, {"family": "Svindland", "given": "Aud", "initials": "A"}, {"family": "Kallioniemi", "given": "Olli", "initials": "O"}, {"family": "Guren", "given": "Marianne G", "initials": "MG"}, {"family": "Nesbakken", "given": "Arild", "initials": "A"}, {"family": "Almeida", "given": "Raquel", "initials": "R"}, {"family": "Lothe", "given": "Ragnhild A", "initials": "RA"}], "type": "journal article", "published": "2018-09-00", "journal": {"title": "Mol Oncol", "issn": "1878-0261", "volume": "12", "issue": "9", "pages": "1639-1655", "issn-l": "1574-7891"}, "abstract": "We aimed to refine the value of CDX2 as an independent prognostic and predictive biomarker in colorectal cancer (CRC) according to disease stage and chemotherapy sensitivity in preclinical models. CDX2 expression was evaluated in 1045 stage I-IV primary CRCs by gene expression (n\u00a0=\u00a0403) or immunohistochemistry (n\u00a0=\u00a0642) and in relation to 5-year relapse-free survival (RFS), overall survival (OS), and chemotherapy. Pharmacogenomic associations between CDX2 expression and 69 chemotherapeutics were assessed by drug screening of 35 CRC cell lines. CDX2 expression was lost in 11.6% of cases and showed independent poor prognostic value in multivariable models. For individual stages, CDX2 was prognostic only in stage IV, independent of chemotherapy. Among stage I-III patients not treated in an adjuvant setting, CDX2 loss was associated with a particularly poor survival in the BRAF-mutated subgroup, but prognostic value was independent of microsatellite instability status and the consensus molecular subtypes. In stage III, the 5-year RFS rate was higher among patients with loss of CDX2 who received adjuvant chemotherapy than among patients who did not. The CDX2-negative cell lines were significantly more sensitive to chemotherapeutics than CDX2-positive cells, and the multidrug resistance genes MDR1 and CFTR were significantly downregulated both in CDX2-negative cells and in patient tumors. Loss of CDX2 in CRC is an adverse prognostic biomarker only in stage IV disease and appears to be associated with benefit from adjuvant chemotherapy in stage III. Early-stage patients not qualifying for chemotherapy might be reconsidered for such treatment if their tumor has loss of CDX2 and mutated BRAF.", "doi": "10.1002/1878-0261.12347", "pmid": "29900672", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pmc", "key": "PMC6120232"}], "notes": [], "created": "2019-01-17T14:01:49.883Z", "modified": "2019-01-17T14:01:49.902Z"}, {"entity": "publication", "iuid": "ef604217a274449eb05dc2491e51c976", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/ef604217a274449eb05dc2491e51c976.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/ef604217a274449eb05dc2491e51c976"}}, "title": "A fine-needle aspiration-based protein signature discriminates benign from malignant breast lesions.", "authors": [{"family": "Franz\u00e9n", "given": "Bo", "initials": "B"}, {"family": "Kamali-Moghaddam", "given": "Masood", "initials": "M"}, {"family": "Alexeyenko", "given": "Andrey", "initials": "A"}, {"family": "Hatschek", "given": "Thomas", "initials": "T"}, {"family": "Becker", "given": "Susanne", "initials": "S"}, {"family": "Wik", "given": "Lotta", "initials": "L"}, {"family": "Kierkegaard", "given": "Jonas", "initials": "J"}, {"family": "Eriksson", "given": "Annika", "initials": "A"}, {"family": "Muppani", "given": "Naveen R", "initials": "NR"}, {"family": "Auer", "given": "Gert", "initials": "G"}, {"family": "Landegren", "given": "Ulf", "initials": "U"}, {"family": "Lewensohn", "given": "Rolf", "initials": "R"}], "type": "journal article", "published": "2018-09-00", "journal": {"title": "Mol Oncol", "issn": "1878-0261", "volume": "12", "issue": "9", "pages": "1415-1428", "issn-l": "1574-7891"}, "abstract": "There are increasing demands for informative cancer biomarkers, accessible via minimally invasive procedures, both for initial diagnostics and to follow-up personalized cancer therapy. Fine-needle aspiration (FNA) biopsy provides ready access to relevant tissues; however, the minute sample amounts require sensitive multiplex molecular analysis to achieve clinical utility. We have applied proximity extension assays (PEA) and NanoString (NS) technology for analyses of proteins and of RNA, respectively, in FNA samples. Using samples from patients with breast cancer (BC, n\u00a0=\u00a025) or benign lesions (n\u00a0=\u00a033), we demonstrate that these FNA-based molecular analyses (a) can offer high sensitivity and reproducibility, (b) may provide correct diagnosis in shorter time and at a lower cost than current practice, (c) correlate with results from routine analysis (i.e., benchmarking against immunohistochemistry tests for ER, PR, HER2, and Ki67), and (d) may also help identify new markers related to immunotherapy. A specific 11-protein signature, including FGF binding protein 1, decorin, and furin, distinguished all cancer patient samples from all benign lesions in our main cohort and in smaller replication cohort. Due to the minimally traumatic sampling and rich molecular information, this combined proteomics and transcriptomic methodology is promising for diagnostics and evaluation of treatment efficacy in BC.", "doi": "10.1002/1878-0261.12350", "pmid": "30019538", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pmc", "key": "PMC6120227"}], "notes": [], "created": "2019-01-17T14:01:45.368Z", "modified": "2019-01-17T14:01:45.387Z"}, {"entity": "publication", "iuid": "d0929650e1a94e0a900ebd641c5a056f", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/d0929650e1a94e0a900ebd641c5a056f.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/d0929650e1a94e0a900ebd641c5a056f"}}, "title": "Genomewide binding of transcription factor Snail1 in triple-negative breast cancer cells.", "authors": [{"family": "Maturi", "given": "Varun", "initials": "V"}, {"family": "Mor\u00e9n", "given": "Anita", "initials": "A"}, {"family": "Enroth", "given": "Stefan", "initials": "S"}, {"family": "Heldin", "given": "Carl-Henrik", "initials": "CH"}, {"family": "Moustakas", "given": "Aristidis", "initials": "A"}], "type": "journal article", "published": "2018-06-00", "journal": {"title": "Mol Oncol", "issn": "1878-0261", "volume": "12", "issue": "7", "pages": "1153-1174", "issn-l": "1574-7891"}, "abstract": "Transcriptional regulation mediated by the zinc finger protein Snail1 controls early embryogenesis. By binding to the epithelial tumor suppressor CDH1 gene, Snail1 initiates the epithelial-mesenchymal transition (EMT). The EMT generates stem-like cells and promotes invasiveness during cancer progression. Accordingly, Snail1 mRNA and protein is abundantly expressed in triple-negative breast cancers with enhanced metastatic potential and phenotypic signs of the EMT. Such high endogenous Snail1 protein levels permit quantitative chromatin immunoprecipitation-sequencing (ChIP-seq) analysis. Snail1 associated with 185 genes at cis regulatory regions in the Hs578T triple-negative breast cancer cell model. These genes include morphogenetic regulators and signaling components that control polarized differentiation. Using the CRISPR/Cas9 system in Hs578T cells, a double deletion of 10\u00a0bp each was engineered into the first exon and into the second exon-intron junction of Snail1, suppressing Snail1 expression and causing misregulation of several hundred genes. Specific attention to regulators of chromatin organization provides a possible link to new phenotypes uncovered by the Snail1 loss-of-function mutation. On the other hand, genetic inactivation of Snail1 was not sufficient to establish a full epithelial transition to these tumor cells. Thus, Snail1 contributes to the malignant phenotype of breast cancer cells via diverse new mechanisms.", "doi": "10.1002/1878-0261.12317", "pmid": "29729076", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pmc", "key": "PMC6026864"}], "notes": [], "created": "2019-01-17T13:52:20.885Z", "modified": "2019-01-17T13:52:20.904Z"}, {"entity": "publication", "iuid": "488c3f1e3530424fbd14b7389df2392b", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/488c3f1e3530424fbd14b7389df2392b.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/488c3f1e3530424fbd14b7389df2392b"}}, "title": "Bioinformatory-assisted analysis of next-generation sequencing data for precision medicine in pancreatic cancer.", "authors": [{"family": "Malgerud", "given": "Linn\u00e9a", "initials": "L"}, {"family": "Lindberg", "given": "Johan", "initials": "J"}, {"family": "Wirta", "given": "Valtteri", "initials": "V"}, {"family": "Gustafsson-Liljefors", "given": "Maria", "initials": "M"}, {"family": "Karimi", "given": "Masoud", "initials": "M"}, {"family": "Moro", "given": "Carlos Fern\u00e1ndez", "initials": "CF"}, {"family": "Stecker", "given": "Katrin", "initials": "K"}, {"family": "Picker", "given": "Alexander", "initials": "A"}, {"family": "Huelsewig", "given": "Carolin", "initials": "C"}, {"family": "Stein", "given": "Martin", "initials": "M"}, {"family": "Bohnert", "given": "Regina", "initials": "R"}, {"family": "Del Chiaro", "given": "Marco", "initials": "M"}, {"family": "Haas", "given": "Stephan L", "initials": "SL"}, {"family": "Heuchel", "given": "Rainer L", "initials": "RL"}, {"family": "Permert", "given": "Johan", "initials": "J"}, {"family": "Maeurer", "given": "Markus J", "initials": "MJ"}, {"family": "Brock", "given": "Stephan", "initials": "S"}, {"family": "Verbeke", "given": "Caroline S", "initials": "CS"}, {"family": "Engstrand", "given": "Lars", "initials": "L"}, {"family": "Jackson", "given": "David B", "initials": "DB"}, {"family": "Gr\u00f6nberg", "given": "Henrik", "initials": "H"}, {"family": "L\u00f6hr", "given": "Johannes Matthias", "initials": "JM"}], "type": "journal article", "published": "2017-10-00", "journal": {"title": "Mol Oncol", "issn": "1878-0261", "volume": "11", "issue": "10", "pages": "1413-1429", "issn-l": "1574-7891"}, "abstract": "Pancreatic ductal adenocarcinoma (PDAC) is a tumor with an extremely poor prognosis, predominantly as a result of chemotherapy resistance and numerous somatic mutations. Consequently, PDAC is a prime candidate for the use of sequencing to identify causative mutations, facilitating subsequent administration of targeted therapy. In a feasibility study, we retrospectively assessed the therapeutic recommendations of a novel, evidence-based software that analyzes next-generation sequencing (NGS) data using a large panel of pharmacogenomic biomarkers for efficacy and toxicity. Tissue from 14 patients with PDAC was sequenced using NGS with a 620 gene panel. FASTQ files were fed into treatmentmap. The results were compared with chemotherapy in the patients, including all side effects. No changes in therapy were made. Known driver mutations for PDAC were confirmed (e.g. KRAS, TP53). Software analysis revealed positive biomarkers for predicted effective and ineffective treatments in all patients. At least one biomarker associated with increased toxicity could be detected in all patients. Patients had been receiving one of the currently approved chemotherapy agents. In two patients, toxicity could have been correctly predicted by the software analysis. The results suggest that NGS, in combination with an evidence-based software, could be conducted within a 2-week period, thus being feasible for clinical routine. Therapy recommendations were principally off-label use. Based on the predominant KRAS mutations, other drugs were predicted to be ineffective. The pharmacogenomic biomarkers indicative of increased toxicity could be retrospectively linked to reported negative side effects in the respective patients. Finally, the occurrence of somatic and germline mutations in cancer syndrome-associated genes is noteworthy, despite a high frequency of these particular variants in the background population. These results suggest software-analysis of NGS data provides evidence-based information on effective, ineffective and toxic drugs, potentially forming the basis for precision cancer medicine in PDAC.", "doi": "10.1002/1878-0261.12108", "pmid": "28675654", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pmc", "key": "PMC5623817"}, {"db": "figshare", "key": "10.6084/m9.figshare.5311114"}], "notes": [], "created": "2018-12-05T12:52:22.328Z", "modified": "2018-12-05T12:52:22.348Z"}, {"entity": "publication", "iuid": "32449e30fec643bd85167a3be795a9b9", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/32449e30fec643bd85167a3be795a9b9.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/32449e30fec643bd85167a3be795a9b9"}}, "title": "Drug sensitivity and resistance testing identifies PLK1 inhibitors and gemcitabine as potent drugs for malignant peripheral nerve sheath tumors.", "authors": [{"family": "Kolberg", "given": "Matthias", "initials": "M"}, {"family": "Bruun", "given": "Jarle", "initials": "J"}, {"family": "Murum\u00e4gi", "given": "Astrid", "initials": "A"}, {"family": "Mpindi", "given": "John P", "initials": "JP"}, {"family": "Bergsland", "given": "Christian H", "initials": "CH"}, {"family": "H\u00f8land", "given": "Maren", "initials": "M"}, {"family": "Eilertsen", "given": "Ina A", "initials": "IA"}, {"family": "Danielsen", "given": "Stine A", "initials": "SA"}, {"family": "Kallioniemi", "given": "Olli", "initials": "O"}, {"family": "Lothe", "given": "Ragnhild A", "initials": "RA"}], "type": "journal article", "published": "2017-09-00", "journal": {"title": "Mol Oncol", "issn": "1878-0261", "volume": "11", "issue": "9", "pages": "1156-1171", "issn-l": "1574-7891"}, "abstract": "Patients with malignant peripheral nerve sheath tumor (MPNST), a rare soft tissue cancer associated with loss of the tumor suppressor neurofibromin (NF1), have poor prognosis and typically respond poorly to adjuvant therapy. We evaluated the effect of 299 clinical and investigational compounds on seven MPNST cell lines, two primary cultures of human Schwann cells, and five normal bone marrow aspirates, to identify potent drugs for MPNST treatment with few side effects. Top hits included Polo-like kinase 1 (PLK1) inhibitors (volasertib and BI2536) and the fluoronucleoside gemcitabine, which were validated in orthogonal assays measuring viability, cytotoxicity, and apoptosis. DNA copy number, gene expression, and protein expression were determined for the cell lines to assess pharmacogenomic relationships. MPNST cells were more sensitive to BI2536 and gemcitabine compared to a reference set of 94 cancer cell lines. PLK1, RRM1, and RRM2 mRNA levels were increased in MPNST compared to benign neurofibroma tissue, and the protein level of PLK1 was increased in the MPNST cell lines compared to normal Schwann cells, indicating an increased dependence on these drug targets in malignant cells. Furthermore, we observed an association between increased mRNA expression of PLK1, RRM1, and RRM2 in patient samples and worse disease outcome, suggesting a selective benefit from inhibition of these genes in the most aggressive tumors.", "doi": "10.1002/1878-0261.12086", "pmid": "28556483", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pmc", "key": "PMC5579334"}], "notes": [], "created": "2018-12-05T12:56:29.769Z", "modified": "2018-12-05T12:56:29.790Z"}, {"entity": "publication", "iuid": "46820fb7bdc7414d8b8747cbefc31c55", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/46820fb7bdc7414d8b8747cbefc31c55.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/46820fb7bdc7414d8b8747cbefc31c55"}}, "title": "Replication stress, DNA damage signalling, and cytomegalovirus infection in human medulloblastomas.", "authors": [{"family": "Bartek", "given": "Jiri", "initials": "J"}, {"family": "Fornara", "given": "Olesja", "initials": "O"}, {"family": "Merchut-Maya", "given": "Joanna Maria", "initials": "JM"}, {"family": "Maya-Mendoza", "given": "Apolinar", "initials": "A"}, {"family": "Rahbar", "given": "Afshar", "initials": "A"}, {"family": "Stragliotto", "given": "Giuseppe", "initials": "G"}, {"family": "Broholm", "given": "Helle", "initials": "H"}, {"family": "Svensson", "given": "Mikael", "initials": "M"}, {"family": "Sehested", "given": "Astrid", "initials": "A"}, {"family": "S\u00f6derberg Naucler", "given": "Cecilia", "initials": "C"}, {"family": "Bartkova", "given": "Jirina", "initials": "J"}], "type": "journal article", "published": "2017-08-00", "journal": {"title": "Mol Oncol", "issn": "1878-0261", "volume": "11", "issue": "8", "pages": "945-964", "issn-l": "1574-7891"}, "abstract": "Medulloblastomas are the most common, and often fatal, paediatric brain tumours that feature high genomic instability, frequent infection by human cytomegalovirus (HCMV) and resistance to radiation and chemotherapy. The causes of the pronounced chromosomal instability and its potential links with HCMV infection and/or resistance to genotoxic therapies remain largely unknown. To address these issues, here we have combined immunohistochemical analysis of a series of 25 paediatric medulloblastomas, complemented by medulloblastoma cell culture models including experimental HCMV infection. Using eight established immunohistochemical markers to assess the status of the DDR machinery, we found pronounced endogenous DNA damage signalling (\u03b3H2AX marker) and robust constitutive activation of both the ATM-Chk2 and ATR-Chk1 DNA damage checkpoint kinase cascades, yet unexpectedly modest p53 tumour suppressor activation, across our medulloblastoma cohort. Most tumours showed high proliferation (Ki67 marker), variable oxidative DNA damage (8-oxoguanine lesions) and formation of 53BP1 nuclear 'bodies', the latter indicating (along with ATR-Chk1 signalling) endogenous replication stress. The bulk of the clinical specimens also showed expression of HCMV immediate early and late proteins, in comparative analyses using three immunohistochemical protocols. Cell culture experiments validated the chronic endogenous replication stress in medulloblastoma cell lines and showed sharply differential, intriguing responses of normal cells and medulloblastoma cells to HCMV infection, including differential subcellular mislocalization and enhancement of replication stress-related 53BP1 body formation, the latter in cell-non-autonomous manner. Overall, our results strongly indicate that in human medulloblastomas, the DDR checkpoint barrier is widely activated, at least in part due to replication stress. Furthermore, we propose that unorthodox p53 defects other than mutations may allow high proliferation despite the ongoing checkpoint signalling and that the highly prevalent HCMV may impact the medulloblastoma host cell replication stress and DNA repair. Collectively, the scenario we report here likely fuels genomic instability and evolution of medulloblastoma resistance to standard-of-care genotoxic treatments.", "doi": "10.1002/1878-0261.12061", "pmid": "28383788", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pmc", "key": "PMC5537913"}], "notes": [], "created": "2018-12-05T12:10:15.674Z", "modified": "2018-12-05T12:10:15.692Z"}, {"entity": "publication", "iuid": "22cebddd1f1548bfbca843cc68eaa6c3", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/22cebddd1f1548bfbca843cc68eaa6c3.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/22cebddd1f1548bfbca843cc68eaa6c3"}}, "title": "DNA damage signalling barrier, oxidative stress and treatment-relevant DNA repair factor alterations during progression of human prostate cancer.", "authors": [{"family": "Kurfurstova", "given": "Daniela", "initials": "D"}, {"family": "Bartkova", "given": "Jirina", "initials": "J"}, {"family": "Vrtel", "given": "Radek", "initials": "R"}, {"family": "Mickova", "given": "Alena", "initials": "A"}, {"family": "Burdova", "given": "Alena", "initials": "A"}, {"family": "Majera", "given": "Dusana", "initials": "D"}, {"family": "Mistrik", "given": "Martin", "initials": "M"}, {"family": "Kral", "given": "Milan", "initials": "M"}, {"family": "Santer", "given": "Frederic R", "initials": "FR"}, {"family": "Bouchal", "given": "Jan", "initials": "J"}, {"family": "Bartek", "given": "Jiri", "initials": "J"}], "type": "journal article", "published": "2016-06-00", "journal": {"title": "Mol Oncol", "issn": "1878-0261", "volume": "10", "issue": "6", "pages": "879-894", "issn-l": "1574-7891"}, "abstract": "The DNA damage checkpoints provide an anti-cancer barrier in diverse tumour types, however this concept has remained unexplored in prostate cancer (CaP). Furthermore, targeting DNA repair defects by PARP1 inhibitors (PARPi) as a cancer treatment strategy is emerging yet requires suitable predictive biomarkers. To address these issues, we performed immunohistochemical analysis of multiple markers of DNA damage signalling, oxidative stress, DNA repair and cell cycle control pathways during progression of human prostate disease from benign hyperplasia, through intraepithelial neoplasia to CaP, complemented by genetic analyses of TMPRSS2-ERG rearrangement and NQO1, an anti-oxidant factor and p53 protector. The DNA damage checkpoint barrier (\u03b3H2AX, pATM, p53) mechanism was activated during CaP tumorigenesis, albeit less and with delayed culmination compared to other cancers, possibly reflecting lower replication stress (slow proliferation despite cases of Rb loss and cyclin D1 overexpression) and progressive loss of ATM activator NKX3.1. Oxidative stress (8-oxoguanine lesions) and NQO1 increased during disease progression. NQO1 genotypes of 390 men did not indicate predisposition to CaP, yet loss of NQO1 in CaP suggested potential progression-opposing tumour suppressor role. TMPRSS2-ERG rearrangement and PTEN loss, events sensitizing to PARPi, occurred frequently along with heterogeneous loss of DNA repair factors 53BP1, JMJD1C and Rev7 (all studied here for the first time in CaP) whose defects may cause resistance to PARPi. Overall, our results reveal an unorthodox DNA damage checkpoint barrier scenario in CaP tumorigenesis, and provide novel insights into oxidative stress and DNA repair, with implications for biomarker guidance of future targeted therapy of CaP.", "doi": "10.1016/j.molonc.2016.02.005", "pmid": "26987799", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S1574-7891(16)00037-5"}, {"db": "pmc", "key": "PMC5423169"}], "notes": [], "created": "2018-12-05T09:44:41.156Z", "modified": "2018-12-05T09:44:41.175Z"}, {"entity": "publication", "iuid": "bdd9042a133043e0b762c1a0f7842de8", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/bdd9042a133043e0b762c1a0f7842de8.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/bdd9042a133043e0b762c1a0f7842de8"}}, "title": "Detection of glyco-mucin profiles improves specificity of MUC16 and MUC1 biomarkers in ovarian serous tumours.", "authors": [{"family": "Ricardo", "given": "Sara", "initials": "S"}, {"family": "Marcos-Silva", "given": "Lara", "initials": "L"}, {"family": "Pereira", "given": "Daniela", "initials": "D"}, {"family": "Pinto", "given": "Rita", "initials": "R"}, {"family": "Almeida", "given": "Raquel", "initials": "R"}, {"family": "S\u00f6derberg", "given": "Ola", "initials": "O"}, {"family": "Mandel", "given": "Ulla", "initials": "U"}, {"family": "Clausen", "given": "Henrik", "initials": "H"}, {"family": "Felix", "given": "Ana", "initials": "A"}, {"family": "Lunet", "given": "Nuno", "initials": "N"}, {"family": "David", "given": "Leonor", "initials": "L"}], "type": "journal article", "published": "2015-02-00", "journal": {"title": "Mol Oncol", "issn": "1878-0261", "volume": "9", "issue": "2", "pages": "503-512", "issn-l": "1574-7891"}, "abstract": "The CA125 assay detects circulating MUC16 and is one of the most widely used cancer biomarkers for the follow-up of ovarian cancer. We previously demonstrated that detection of aberrant cancer-associated glycoforms of MUC16 as well as MUC1 in circulation could improve the yield of these serum assays. Our aim was to refine ovarian cancer biomarkers by detection of aberrant glycoforms (Tn, STn, and T) of MUC16 and MUC1 in ovarian cancer tissue using Proximity Ligation Assays (PLA). We studied two series of serous ovarian tumours, a pilot series of 66 ovarian tumours (27 cystadenomas, 16 borderline tumours and 23 adenocarcinomas) from Centro Hospitalar S. Jo\u00e3o, Porto and a validation series of 89 ovarian tumours (17 cystadenomas, 25 borderline tumours and 47 adenocarcinomas) from the Portuguese Institute of Oncology Francisco Gentil, Lisbon. PLA reactions for MUC16/Tn, MUC16/STn, MUC1/Tn and MUC1/STn were negative in benign lesions but often positive in borderline and malignant lesions, in both series. An even better yield was obtained based on positivity for any of the four glyco-mucin profiles, further increasing sensitivity to 72% and 83% in the two series, respectively, with 100% specificity. The strategy is designated glyco-mucin profiling and provides strong support for development of PLA-based serum assays for early diagnosis.", "doi": "10.1016/j.molonc.2014.10.005", "pmid": "25454345", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S1574-7891(14)00244-0"}, {"db": "pmc", "key": "PMC5528651"}], "notes": [], "created": "2018-12-05T09:29:09.895Z", "modified": "2018-12-05T09:29:09.914Z"}, {"entity": "publication", "iuid": "0b32e64e152449fe825664444602e473", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/0b32e64e152449fe825664444602e473.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/0b32e64e152449fe825664444602e473"}}, "title": "Garbage in, garbage out: a critical evaluation of strategies used for validation of immunohistochemical biomarkers.", "authors": [{"family": "O'Hurley", "given": "Gillian", "initials": "G"}, {"family": "Sj\u00f6stedt", "given": "Evelina", "initials": "E"}, {"family": "Rahman", "given": "Arman", "initials": "A"}, {"family": "Li", "given": "Bo", "initials": "B"}, {"family": "Kampf", "given": "Caroline", "initials": "C"}, {"family": "Pont\u00e9n", "given": "Fredrik", "initials": "F"}, {"family": "Gallagher", "given": "William M", "initials": "WM"}, {"family": "Lindskog", "given": "Cecilia", "initials": "C"}], "type": "evaluation studies", "published": "2014-06-00", "journal": {"title": "Mol Oncol", "issn": "1878-0261", "volume": "8", "issue": "4", "pages": "783-798", "issn-l": "1574-7891"}, "abstract": "The use of immunohistochemistry (IHC) in clinical cohorts is of paramount importance in determining the utility of a biomarker in clinical practice. A major bottleneck in translating a biomarker from bench-to-bedside is the lack of well characterized, specific antibodies suitable for IHC. Despite the widespread use of IHC as a biomarker validation tool, no universally accepted standardization guidelines have been developed to determine the applicability of particular antibodies for IHC prior to its use. In this review, we discuss the technical challenges faced by the use of immunohistochemical biomarkers and rigorously explore classical and emerging antibody validation technologies. Based on our review of these technologies, we provide strict criteria for the pragmatic validation of antibodies for use in immunohistochemical assays. ", "doi": "10.1016/j.molonc.2014.03.008", "pmid": "24725481", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S1574-7891(14)00056-8"}, {"db": "pmc", "key": "PMC5528533"}], "notes": [], "created": "2018-12-05T09:10:26.024Z", "modified": "2018-12-05T09:10:26.043Z"}, {"entity": "publication", "iuid": "c35fb72f70d040f28b3b88c69be86fc9", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/c35fb72f70d040f28b3b88c69be86fc9.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/c35fb72f70d040f28b3b88c69be86fc9"}}, "title": "The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings.", "authors": [{"family": "Helleday", "given": "Thomas", "initials": "T"}], "type": "journal article", "published": "2011-08-00", "journal": {"title": "Mol Oncol", "issn": "1878-0261", "volume": "5", "issue": "4", "pages": "387-393", "issn-l": "1574-7891"}, "abstract": "Poly (ADP-ribose) polymerase (PARP) inhibitors effectively kill tumours defective in the BRCA1 or BRCA2 genes through the concept of synthetic lethality. It is suggested that PARP inhibitors cause an increase in DNA single-strand breaks (SSBs), which are converted during replication to irreparable toxic DNA double-strand breaks (DSBs) in BRCA1/2 defective cells. There are a number of recent reports challenging this model. Here, alternative models that are not mutually exclusive are presented to explain the synthetic lethality between BRCA1/2 and PARP inhibitors. One such model proposes that PARP inhibition causes PARP-1 to be trapped onto DNA repair intermediates, especially during base excision repair. This may in turn cause obstruction to replication forks, which require BRCA-dependent homologous recombination to be resolved. In another model, PARP is directly involved in catalysing replication repair in a distinct pathway from homologous recombination. Experimental evidence supporting these novel models to explain the PARP-BRCA synthetic lethality are discussed.", "doi": "10.1016/j.molonc.2011.07.001", "pmid": "21821475", "labels": {"Affiliated researcher": null}, "xrefs": [{"db": "pii", "key": "S1574-7891(11)00074-3"}, {"db": "pmc", "key": "PMC5528309"}], "notes": [], "created": "2018-12-05T08:26:33.503Z", "modified": "2018-12-05T08:26:33.535Z"}], "created": "2018-12-05T08:26:33.517Z", "modified": "2020-11-27T13:12:57.795Z"}