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  • 1.
    Arnberg, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kidd, Alistair H
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Edlund, Karin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Pring-Åkerblom, Patricia
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Adenovirus type 37 binds to cell surface sialic acid through a charge-dependent interaction2002In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 302, no 1, p. 33-43Article in journal (Refereed)
    Abstract [en]

    Most adenoviruses use the coxsackie-adenovirus receptor (CAR) as a major cellular receptor. We have shown recently that adenovirus types 8, 19a, and 37, which are the major causes of epidemic keratoconjunctivitis, use sialic acid rather than CAR as a major cellular receptor. The predicted isoelectric point of the receptor-interacting knob domain in the adenovirus fiber protein is unusually high (9.0-9.1) in type 8, 19a, and 37. The pKa of sialic acid is low, 2.6, implying a possible involvement of charge in fiber knob-sialic acid interactions. Here we show that (i) positively charged adenovirus knobs require sialic acid for efficient cell membrane interactions; (ii) viral and knob interactions with immobilized sialic acid or cell-surface sialic acid are sensitive to increased ionic strength; (iii) negatively charged molecules such as sulfated glycosaminoglycans inhibit the binding of virions to target cells in a nonspecific, charge-dependent manner; and that (iv) the ability of adenovirus knobs to interact with sialic acid correlates with the overall charge on the top surface of the respective knobs as predicted by homology modeling. Taken together, the results presented provide strong evidence for a charge mechanism during the interaction between the Ad37 fiber knob and sialic acid.

  • 2. Badr, Christian E
    et al.
    Wurdinger, Thomas
    Nilsson, Jonas
    Neuro-oncology Research Group, Department of Neurosurgery, VU University Medical Center, Amsterdam, Netherlands.
    Niers, Johanna M
    Whalen, Michael
    Degterev, Alexei
    Tannous, Bakhos A
    Lanatoside C sensitizes glioblastoma cells to tumor necrosis factor-related apoptosis-inducing ligand and induces an alternative cell death pathway.2011In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 13, no 11, p. 1213-1224Article in journal (Refereed)
    Abstract [en]

    Human glioblastoma (GBM) cells are notorious for their resistance to apoptosis-inducing therapeutics. We have identified lanatoside C as a sensitizer of GBM cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death partly by upregulation of the death receptor 5. We show that lanatoside C sensitizes GBM cells to TRAIL-induced apoptosis in a GBM xenograft model in vivo. Lanatoside C on its own serves as a therapeutic agent against GBM by activating a caspase-independent cell death pathway. Cells treated with lanatoside C showed necrotic cell morphology with absence of caspase activation, low mitochondrial membrane potential, and early intracellular ATP depletion. In conclusion, lanatoside C sensitizes GBM cells to TRAIL-induced cell death and mitigates apoptosis resistance of glioblastoma cells by inducing an alternative cell death pathway. To our knowledge, this is one of the first examples of use of caspase-independent cell death inducers to trigger tumor regression in vivo. Activation of such mechanism may be a useful strategy to counter resistance of cancer cells to apoptosis.

  • 3. Best, Myron G.
    et al.
    Sol, Nik
    Kooi, Irsan
    Tannous, Jihane
    Westerman, Bart A.
    Rustenburg, Francois
    Schellen, Pepijn
    Verschueren, Heleen
    Post, Edward
    Koster, Jan
    Ylstra, Bauke
    Ameziane, Najim
    Dorsman, Josephine
    Smit, Egbert F.
    Verheul, Henk M.
    Noske, David P.
    Reijneveld, Jaap C.
    Nilsson, R. Jonas A.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tannous, Bakhos A.
    Wesseling, Pieter
    Wurdinger, Thomas
    RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics2015In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 28, no 5, p. 666-676Article in journal (Refereed)
    Abstract [en]

    Tumor-educated blood platelets (TEPs) are implicated as central players in the systemic and local responses to tumor growth, thereby altering their RNA profile. We determined the diagnostic potential of TEPs by mRNA sequencing of 283 platelet samples. We distinguished 228 patients with localized and metastasized tumors from 55 healthy individuals with 96% accuracy. Across six different tumor types, the location of the primary tumor was correctly identified with 71% accuracy. Also, MET or HER2-positive, and mutant KRAS, EGFR, or PIK3CA tumors were accurately distinguished using surrogate TEP mRNA profiles. Our results indicate that blood platelets provide a valuable platform for pan-cancer, multiclass cancer, and companion diagnostics, possibly enabling clinical advances in blood-based "liquid biopsies".

  • 4. Best, Myron G.
    et al.
    Sol, Nik
    't Veld, Sjors G. J. G. In
    Vancura, Adrienne
    Muller, Mirte
    Niemeijer, Anna-Larissa N.
    Fejes, Aniko V.
    Tjon Kon Fat, Lee-Ann
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    't Veld, Anna E. Huis In
    Leurs, Cyra
    Le Large, Tessa Y.
    Meijer, Laura L.
    Kooi, Irsan E.
    Rustenburg, Francois
    Schellen, Pepijn
    Verschueren, Heleen
    Post, Edward
    Wedekind, Laurine E.
    Bracht, Jillian
    Esenkbrink, Michelle
    Wils, Leon
    Favaro, Francesca
    Schoonhoven, Jilian D.
    Tannous, Jihane
    Meijers-Heijboer, Hanne
    Kazemier, Geert
    Giovannetti, Elisa
    Reijneveld, Jaap C.
    Idema, Sander
    Killestein, Joep
    Heger, Michal
    de Jager, Saskia C.
    Urbanus, Rolf T.
    Hoefer, Imo E.
    Pasterkamp, Gerard
    Mannhalter, Christine
    Gomez-Arroyo, Jose
    Bogaard, Harm-Jan
    Noske, David P.
    Vandertop, W. Peter
    van den Broek, Daan
    Ylstra, Bauke
    Nilsson, Jonas A.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Vrije Univ Amsterdam Med Ctr, Canc Ctr Amsterdam, Dept Neurosurg, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands.
    Wesseling, Pieter
    Karachaliou, Niki
    Rosell, Rafael
    Lee-Lewandrowski, Elizabeth
    Lewandrowski, Kent B.
    Tannous, Bakhos A.
    de Langen, Adrianus J.
    Smit, Egbert F.
    van den Heuvel, Michel M.
    Wurdinger, Thomas
    Swarm Intelligence-Enhanced Detection of Non-Small-Cell Lung Cancer Using Tumor-Educated Platelets2017In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 32, no 2, p. 238-252Article in journal (Refereed)
    Abstract [en]

    Blood-based liquid biopsies, including tumor-educated blood platelets (TEPs), have emerged as promising biomarker sources for non-invasive detection of cancer. Here we demonstrate that particle-swarm optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA sequencing libraries (n = 779). This resulted in accurate TEP-based detection of early- and late-stage non-small-cell lung cancer (n = 518 late-stage validation cohort, accuracy, 88%; AUC, 0.94; 95% CI, 0.92-0.96; p < 0.001; n = 106 early-stage validation cohort, accuracy, 81%; AUC, 0.89; 95% CI, 0.83-0.95; p < 0.001), independent of age of the individuals, smoking habits, whole-blood storage time, and various inflammatory conditions. PSO enabled selection of gene panels to diagnose cancer from TEPs, suggesting that swarm intelligence may also benefit the optimization of diagnostics readout of other liquid biopsy biosources.

  • 5.
    Best, Myron
    et al.
    VU Medical Center, Amsterdam, Netherlands.
    Sol, Nik
    VU Medical Center, Amsterdam, Netherlands.
    Kooi, Irsan
    VU Medical Center, Amsterdam, Netherlands.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Westerman, Bart
    VU Medical Center, Amsterdam, Netherlands.
    Yistra, Bauke
    VU Medical Center, Amsterdam, Netherlands.
    Dorsman, Josephine
    VU Medical Center, Amsterdam, Netherlands.
    Smit, Egbert
    VU Medical Center, Amsterdam, Netherlands.
    Verheui, Henk
    VU Medical Center, Amsterdam, Netherlands.
    Reijneveld, Jaap
    VU Medical Center, Amsterdam, Netherlands.
    Tannous, Bakhos
    Massachusetts General Hospital, Boston, MA, USA.
    Wesseling, Pieter
    VU Medical Center, Amsterdam, Netherlands.
    Wurdinger, Thomas
    VU Medical Center, Amsterdam, Netherlands.
    Tumor-educated platelets allow for multiclass liquid biopsy-based diagnosis of cancer2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no Suppl. 15, article id LB-124Article in journal (Other academic)
  • 6. Best, Myron
    et al.
    Sol, Nik
    Kooi, Irsan
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Westerman, Bart
    Ylstra, Bauke
    Dorsman, Josephine
    Smit, Egbert F
    Verheul, Henk M W
    Reijneveld, Jaap C
    Tannous, Bakhos A
    Wesseling, Pieter
    Wurdinger, Thomas
    Allowance of tumor-educated platelets for multiclass liquid biopsy-based diagnosis of cancer2015In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 33, no 15, suppl., article id 11058Article in journal (Other academic)
  • 7. Bijnsdorp, Irene V.
    et al.
    Hodzic, Jasmina
    Lagerweij, Tonny
    Westerman, Bart
    Krijgsman, Oscar
    Broeke, Jurjen
    Verweij, Frederik
    Nilsson, R. Jonas A.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
    Rozendaal, Lawrence
    van Beusechem, Victor W.
    van Moorselaar, Jeroen A.
    Wurdinger, Thomas
    Geldof, Albert A.
    miR-129-3p controls centrosome number in metastatic prostate cancer cells by repressing CP1102016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 13, p. 16676-16687Article in journal (Refereed)
    Abstract [en]

    The centrosome plays a key role in cancer invasion and metastasis. However, it is unclear how abnormal centrosome numbers are regulated when prostate cancer (PCa) cells become metastatic. CP110 was previously described for its contribution of centrosome amplification (CA) and early development of aggressive cell behaviour. However its regulation in metastatic cells remains unclear. Here we identified miR-129-3p as a novel metastatic microRNA. CP110 was identified as its target protein. In PCa cells that have metastatic capacity, CP110 expression was repressed by miR-129-3p. High miR-129-3p expression levels increased cell invasion, while increasing CP110 levels decreased cell invasion. Overexpression of CP110 in metastatic PCa cells resulted in a decrease in the number of metastasis. In tissues of PCa patients, low CP110 and high miR-129-3p expression levels correlated with metastasis, but not with the expression of genes related to EMT. Furthermore, overexpression of CP110 in metastatic PCa cells resulted in excessive-CA (E-CA), and a change in F-actin distribution which is in agreement with their reduced metastatic capacity. Our data demonstrate that miR-129-3p functions as a CA gatekeeper in metastatic PCa cells by maintaining pro-metastatic centrosome amplification (CA) and preventing anti-metastatic E-CA.

  • 8.
    Guo, Dongsheng
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Haapasalo, Hannu
    Raheem, Olayinka
    Bergenheim, Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Perinuclear leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1-3) as prognostic indicators in astrocytic tumors2006In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 111, no 3, p. 238-346Article in journal (Refereed)
    Abstract [en]

    We have previously characterized three human leucine-rich repeats and immunoglobulin-like domains (LRIG) genes and proteins, named LRIG1-3 and proposed that they may act as suppressors of tumor growth. The LRIG1 transmembrane protein antagonizes the activity of epidermal growth factor receptor family receptor tyrosine kinases. In this study, we evaluated the mRNA expression level of LRIG1-3 in human glioma cell lines and control-matched glioma tissues, characterized the sub-cellular localization of an LRIG3–GFP fusion protein, and analyzed the relationship between sub-cellular localization of LRIG1-3 and clinical parameters in 404 astrocytic tumors by immunohistochemistry. LRIG1-3 mRNA was detected in all human glioma cell lines and matched glioma samples, with large differences in the expression levels. Ectopically expressed LRIG3–GFP localized to perinuclear and cytoplasmic compartments, and to the cell surface of transfected glioma cells. Perinuclear staining of LRIG1-3 was associated with low WHO grade and better survival of the patients. Perinuclear staining of LRIG3 was associated with a lower proliferation index and was in addition to tumor grade, an independent prognostic factor. Furthermore, within the groups of grade III and grade IV tumors, perinuclear staining of LRIG3 significantly correlated with better survival. These results indicate that expression and sub-cellular localization of LRIG1-3 might be of importance in the pathogenesis and prognosis of astrocytic tumors.

  • 9. Gur, Gal
    et al.
    Rubin, Chanan
    Katz, Menachem
    Amit, Ido
    Citri, Ami
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Amariglio, Ninette
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Rechavi, Gideon
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Wides, Ron
    Yarden, Yosef
    LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation2004In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 23, no 16, p. 3270-3281Article in journal (Refereed)
  • 10.
    Hedman, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Guo, Dongsheng
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Is LRIG1 a tumour suppressor gene at chromosome 3p14.3?2002In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 41, no 4, p. 352-354Article in journal (Refereed)
    Abstract [en]

    The LRIG1 gene (formerly LIG-1), recently cloned by us, displays structural similarities to the Drosophila Kek I gene. Kek I encodes a cell surface protein, Kekkon-1, which inhibits epidermal growth factor receptor-mediated signalling. We localized the LRIG1 gene to chromosome band 3p14.3, a region known to be deleted in various human cancers. In the present study LRIG1 gene expression was examined in different tumour cell lines and corresponding normal tissues by real-time RT-PCR. In many tumour cell lines, LRIG1 expression appeared absent or was down regulated compared to corresponding normal tissues. The results are consistent with LRIG1 being a tumour suppressor gene in humans. However, further studies are justified to elucidate the explicit role of LRIG1 as a negative regulator of oncogenesis.

  • 11.
    Holgersson, Georg
    et al.
    Institutionen för Immunologi, Genitik och Patologi Umeå Universitet /Centrum för forskning och utveckling Region Gävleborg.
    Bergström, Stefan
    Institutionen för Immunologi, Genitik och Patologi Umeå Universitet /Centrum för forskning och utveckling Region Gävleborg.
    Hallqvist, Anders
    Institutionen för Onkologi, Sahlgrenska Universitetssjukhuset.
    Liv, Per
    Centrum för forskning och utveckling Region Gävleborg.
    Nilsson, R. Jonas A.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Centrum för forskning och utveckling, Uppsala Universitet / Region Gävleborg, Gävle sjukhus, Gävle, Sverige.
    Willén, Linda
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Centrum för forskning och utveckling, Uppsala Universitet / Region Gävleborg, Gävle sjukhus, Gävle, Sverige.
    Nyman, Jan
    Institutionen för Onkologi, Sahlgrenska Universitetssjukhuset.
    Ekman, Simon
    Institutionen för Onkologi, Karolinska Universitetssjukhuset.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Centrum för forskning och utveckling Region Gävleborg.
    The prognostic value of pre-treatment thrombocytosis in two cohorts of patients with non-small cell lung cancer treated with curatively intended chemoradiotherapy2017In: Neoplasma (Bratislava), ISSN 0028-2685, E-ISSN 1338-4317, Vol. 64, no 6, p. 909-915Article in journal (Refereed)
    Abstract [en]

    Chemoradiotherapy is the standard of care for inoperable stage III non-small cell lung cancer (NSCLC). This treatment, however, offers only a small chance of cure and is associated with many side effects. Little research has been made concerning which patients benefit most/least from the treatment. The present study evaluates the prognostic value of anemia, leukocytosis and thrombocytosis at diagnosis in this treatment setting. In the present study, data were collected retrospectively for 222 patients from two different phase II studies conducted between 2002-2007 in Sweden with patients treated with chemoradiotherapy for stage IIIA-IIIB NSCLC. Clinical data and the serum values of hemoglobin (Hgb), White blood cells (WBC) and Platelets (Plt) at enrollment were collected for all patients and studied in relation to overall survival using Kaplan-Meier product-limit estimates and a multivariate Cox proportional hazards regression model. The results showed that patients with thrombocytosis (Plt > 350 x 109 /L) had a shorter median overall survival (14.5 months) than patients with normal Plt at baseline (23.7 months). Patients with leukocytosis (WBC > 9 x 109 /L) had a shorter median survival (14.9 months) than patients with a normal WBC at baseline (22.5 months). However, in a multivariate model including all lab parameters and clinical factors, only thrombocytosis and performance status displayed a prognostic significance. In Conclusion, thrombocytosis showed to be an independent prognostic marker associated with shorter overall survival in stage III NSCLC treated with curatively intended chemoradiotherapy. This knowledge can potentially be used together with established prognostic factors, such as performance status when choosing the optimal therapy for the individual patient in this clinical setting

  • 12.
    Holmlund, Camilla
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Guo, Dongsheng
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Starefeldt, Anna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Characterization and tissue-specific expression of human LRIG22004In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 332, p. 35-43Article in journal (Refereed)
    Abstract [en]

    We have recently identified and cloned the human LRIG1 gene (formerly LIG1). LRIG1 is a predicted integral membrane protein with a domain organization reminiscent of the Drosophila epidermal growth factor (EGF)-receptor antagonist Kekkon-1. We have searched for additional members of the human LRIG family and identified LRIG2 (KIAA0806). The LRIG2 gene was localized to chromosome 1p13 and had an open reading frame of 1065 amino acids. The LRIG2 protein was predicted to have the same domain organization as LRIG1 with a signal peptide, an extracellular part containing15 leucine-rich repeats and three immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tail. The LRIG2 amino acid sequence was 47% identical to human LRIG1 and mouse Lrig1 (also known as Lig-1). Northern blotting and RT-PCR revealed LRIG2 transcripts in all tissues analyzed. Quantitative real-time RT-PCR showed the most prominent RNA expression in skin, uterus, ovary, kidney, brain, small intestine, adrenal gland, and stomach. Immunoblotting of COS-7 cell lysates demonstrated that heterologously expressed human LRIG2 had an apparent molecular weight of 132 kDa under reducing gel-running conditions. N-glycosidase F treatment resulted in a reduction of the apparent molecular weight to 107 kDa, showing that LRIG2 was a glycoprotein carrying N-linked oligosaccharides. Cell surface biotinylation experiments and confocal fluorescence laser microscopy demonstrated expression of LRIG2 both at the cell surface and in the cytoplasm. LRIG2 was detected in tissue lysates from stomach, prostate, lung, and fetal brain by immunoblotting. In conclusion, LRIG2 was found to be a glycoprotein which was encoded by a gene on human chromosome 1p13 and its mRNA was present in all tissues analyzed.

  • 13.
    Köhn, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Liquid biopsies in lung cancer: time to implement research technologies in routine care?2017In: Annals of Translational Medicine, ISSN 2305-5839, E-ISSN 2305-5847, Vol. 5, no 13, article id 278Article, review/survey (Refereed)
    Abstract [en]

    Lung cancer is the leading cause of cancer mortality. A substantial progress in the understanding of lung cancer biology has resulted in several promising targeted therapies for advanced disease. Druggable targets today include point mutations such as EGFR, BRAF and re-arrangements in genes such as ALK and ROS1. Liquid biopsies collecting e.g., circulating tumor DNA (ctDNA) reflects overall tumor information and is not biased by analyzing of only a small fraction of the tumor and is always accessible in contrast to the lung cancer tissue. Technological advances in detection of low frequency mutation variants in ctDNA have made it the dominating liquid biopsy platform in terms of utility and sensitivity. Circulating DNA or RNA may possible be used to define populations with higher risk of developing lung cancer, thus reducing screening cohorts and increasing the positive predictive value of screening. Blood based-tests may also aid to identify genetic alterations several weeks prior to radiologically verified recurrence and may be of great value in the follow-up of lung cancer patients. Besides being an alternative to invasive biopsies in selected cases, liquid biopsies offer a unique possibility to monitor treatment response following medical treatment as well as treatment response and resistance development after targeted therapy, giving a possibility to modify the treatment after the genetic profile of the tumor. Ideally, genetic alterations found in ctDNA could be tracked in real-time discriminating between fast-growing life-threatening tumors from more indolent slow growing tumors or premalignant growth that are of no concern for the wellbeing of the patient. This review focuses on future perspectives of liquid biopsies in lung cancer care for different clinical settings and present current technological platforms for further discussion of possible strategies for implementation of liquid biopsies in lung cancer.

  • 14.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    The LRIG-family: identification of novel regulators of ErbB signaling with clinical implications in astrocytoma2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Astrocytic tumors are the most common malignancies of the central nervous system, accounting for more than 60% of all primary brain tumors. The prognosis for high grade astrocytoma patients is dismal and there is no curative treatment, today. A molecular hallmark of astrocytic tumors is dysregulated receptor tyrosine kinase signaling, especially of the epidermal growth factor receptor (EGFR, ErbB1). The aim of the present thesis was to identify endogenous human proteins that downregulate the function of the ErbB1 receptor. We identified a human gene family, the leucine-rich repeats and immunoglobulin-like domains family (LRIG), consisting of LRIG1, LRIG2 and LRIG3, which might fulfill this criterion.

    Two candidates were identified, LRIG1 and LRIG2, which genes were localized to regions frequently deleted in human cancers, chromosome bands 3p14 and 1p13, respectively. LRIG1 and LRIG2 mRNA were expressed in all tissues analyzed, with high expression in brain and other organs. The LRIG mRNA were predicted to encode integral membrane proteins. Antibodies against LRIG1 and LRIG2 were developed and the protein expression was analyzed. LRIG1 was found to have an apparent molecular weight of 143 kDa and was expressed in most tissues with high expression in glandular tissues of the breast and prostate, and the peptic cells of the stomach. LRIG2 was slightly smaller and had an apparent molecular weight of 132 kDa. The LRIG proteins were localized to the cell surface and to perinuclear structures, where LRIG1 co-localized with the trans-Golgi network and early endosomes.

    LRIG1 was found to restrict growth factor signaling by enhancing receptor ubiquitylation and degradation. We showed that LRIG1 interacted with all four members of the ErbB family and induced their downregulation. The interaction with ErbB1 involved both the LRR-domains and the Ig-like domains of LRIG1. LRIG1 enhanced receptor degradation by recruiting the E3 ubiquitin ligase c-Cbl to the LRIG1-ErbB1 complex.

    LRIG1, LRIG2, and LRIG3 were expressed in glioma cell lines and tumor tissues. The LRIG expression was analyzed in 404 astrocytic tumor samples. We found that perinuclear LRIG protein expression correlated with increased survival of patients with astrocytic tumors. Especially perinuclear LRIG3 showed strong correlations with patient survival and tumor cell proliferation index.

    In summary, this thesis contains the discovery and characterization of human LRIG1 and LRIG2. LRIG1 was found to interact with ErbB receptors and downregulate their function. In a clinical material, expression of LRIG proteins correlated with survival in patients with astrocytic tumors.

  • 15.
    Nilsson, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Skog, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nordstrand, Annika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Breakefield, X O
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer.2009In: British journal of cancer, ISSN 1532-1827, Vol. 100, no 10, p. 1603-1607Article in journal (Refereed)
    Abstract [en]

    Herein, we describe a novel approach in the search for prostate cancer biomarkers, which relies on the transcriptome within tumour exosomes. As a proof-of-concept, we show the presence of two known prostate cancer biomarkers, PCA-3 and TMPRSS2:ERG the in exosomes isolated from urine of patients, showing the potential for diagnosis and monitoring cancer patients status.

  • 16.
    Nilsson, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Starefeldt, Anna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    LRIG1 protein in human cells and tissues2003In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 312, no 1, p. 65-71Article in journal (Refereed)
  • 17.
    Nilsson, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Vallbo, Christina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Guo, Dongsheng
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Cloning, characterization and expression of human LIG12001In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 284, no 5, p. 1155-1161Article in journal (Refereed)
    Abstract [en]

    Growth factor receptors are frequently amplified and over-expressed in various human cancers. Recently, a Drosophila cell surface protein, Kekkon-1, was found to participate in an epidermal growth factor (EGF) driven negative feedback loop. Kekkon-1 is induced by EGF, binds to the EGF-receptor, and inhibits receptor-mediated signaling. Here, we have searched for human genes with homologies to Kekkon-1 and identified human LIG1. The gene is the human homologue of mouse Lig-1 and is located on chromosome band 3p14, a region frequently deleted in various human cancers. It is predicted to encode a transmembrane cell-surface protein with extracellular leucine-rich repeats and immunoglobulin-like domains. LIG1 mRNA was detected in all tissues analyzed. The highest and lowest relative expression levels were found in brain and spleen, respectively, and differed by more than 200-fold. Taken together, our data are compatible with a role for LIG1 as a growth and tumor suppressor in human tissues.

  • 18.
    Nilsson, R. Jonas A.
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Balaj, Leonora
    Hulleman, Esther
    van Rijn, Sjoerd
    Pegtel, D. Michiel
    Walraven, Maudy
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gerritsen, Winald R.
    Verheul, Henk M.
    Vandertop, W. Peter
    Noske, David P.
    Skog, Johan
    Wurdinger, Thomas
    Blood platelets contain tumor-derived RNA biomarkers2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 13, p. 3680-3683Article in journal (Refereed)
    Abstract [en]

    Diagnostic platforms providing biomarkers that are highly predictive for diagnosing, monitoring, and stratifying cancer patients are key instruments in the development of personalized medicine. We demonstrate that tumor cells transfer (mutant) RNA into blood platelets in vitro and in vivo, and show that blood platelets isolated from glioma and prostate cancer patients contain the cancer-associated RNA biomarkers EGFRvIII and PCA3, respectively. In addition, gene-expression profiling revealed a distinct RNA signature in platelets from glioma patients compared with normal control subjects. Because platelets are easily accessible and isolated, they may form an attractive platform for the companion diagnostics of cancer.

  • 19.
    Nilsson, R. Jonas A.
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam ; ThromboDx B.V., Amsterdam.
    Karachaliou, Niki
    Berenguer, Jordi
    Gimenez-Capitan, Ana
    Schellen, Pepijn
    Teixido, Cristina
    Tannous, Jihane
    Kuiper, Justine L.
    Drees, Esther
    Grabowska, Magda
    van Keulen, Marte
    Heideman, Danielle A. M.
    Thunnissen, Erik
    Dingemans, Anne-Marie C.
    Viteri, Santiago
    Tannous, Bakhos A.
    Drozdowskyj, Ana
    Rosell, Rafael
    Smit, Egbert F.
    Wurdinger, Thomas
    Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 1, p. 1066-1075Article in journal (Refereed)
    Abstract [en]

    Purpose: Non-small-cell lung cancers harboring EML4-ALK rearrangements are sensitive to crizotinib. However, despite initial response, most patients will eventually relapse, and monitoring EML4-ALK rearrangements over the course of treatment may help identify these patients. However, challenges associated with serial tumor biopsies have highlighted the need for blood-based assays for the monitoring of biomarkers. Platelets can sequester RNA released by tumor cells and are thus an attractive source for the non-invasive assessment of biomarkers. Methods: EML4-ALK rearrangements were analyzed by RT-PCR in platelets and plasma isolated from blood obtained from 77 patients with non-small-cell lung cancer, 38 of whom had EML4-ALK-rearranged tumors. In a subset of 29 patients with EML4-ALK-rearranged tumors who were treated with crizotinib, EML4-ALK rearrangements in platelets were correlated with progression-free and overall survival. Results: RT-PCR demonstrated 65% sensitivity and 100% specificity for the detection of EML4-ALK rearrangements in platelets. In the subset of 29 patients treated with crizotinib, progression-free survival was 3.7 months for patients with EML4-ALK+ platelets and 16 months for those with EML4-ALK- platelets (hazard ratio, 3.5; P = 0.02). Monitoring of EML4-ALK rearrangements in the platelets of one patient over a period of 30 months revealed crizotinib resistance two months prior to radiographic disease progression. Conclusions: Platelets are a valuable source for the non-invasive detection of EML4-ALK rearrangements and may prove useful for predicting and monitoring outcome to crizotinib, thereby improving clinical decisions based on radiographic imaging alone.

  • 20.
    Nordstrand, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tieva, Åse
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Establishment and validation of an in vitro co-culture model to study the interactions between bone and prostate cancer cells2009In: Clinical & experimental metastasis, ISSN 0262-0898, Vol. 26, no 8, p. 945-953Article in journal (Refereed)
    Abstract [en]

    Bone is the preferred site for prostate cancer (PCa) metastases. Once the tumor has established itself within the bone there is virtually no cure. To better understand the interactions between the PCa cells and bone environment in the metastatic process new model systems are needed. We have established a two-compartment in vitro co-culturing model that can be used to follow the trans-activation of bone and/or tumor cells. The model was validated using two PCa tumor cell lines (PC-3; lytic and LNCaP; mixed/osteoblastic) and one osteolytic inducing factor, 1,25-dihydroxyvitamin D(3) (D3). Results were in accordance with the expected bone phenotypes; PC-3 cells and D3 gave osteolytic gene expression profiles in calvariae, with up-regulation of genes needed for osteoclast differentiation, activation and function; Rankl, CathK, Trap and MMP-9, and down-regulation of genes associated with osteoblast differentiation and bone mineralization; Alp, Ocl and Dkk-1. LNCaP cells activated genes in the calvarial bones associated with osteoblast differentiation and mineralization, with marginal effects on osteolytic genes. The results were strengthened by similar changes in protein expression for a selection of the analyzed genes. Furthermore, the osteolytic gene expression profiles in calvarial bones co-cultured with PC-3 cells or with D3 were correlated with the actual ongoing resorptive process, as assessed by the release of collagen fragments from the calvariae. Our results show that the model can be used to follow tumor-induced bone remodeling, and by measuring changes in gene expression in the tumor cells we can also study how they respond to the bone microenvironment.

  • 21. Smits, Michiel
    et al.
    Mir, Shahryar E
    Nilsson, Jonas
    Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
    van der Stoop, Petra M
    Niers, Johanna M
    Marquez, Victor E
    Cloos, Jacqueline
    Breakefield, Xandra O
    Krichevsky, Anna M
    Noske, David P
    Tannous, Bakhos A
    Würdinger, Thomas
    Down-regulation of miR-101 in endothelial cells promotes blood vessel formation through reduced repression of EZH22011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 1, p. e16282-Article in journal (Refereed)
    Abstract [en]

    Angiogenesis is a balanced process controlled by pro- and anti-angiogenic molecules of which the regulation is not fully understood. Besides classical gene regulation, miRNAs have emerged as post-transcriptional regulators of angiogenesis. Furthermore, epigenetic changes caused by histone-modifying enzymes were shown to modulate angiogenesis as well. However, a possible interplay between miRNAs and histone-modulating enzymes during angiogenesis has not been described. Here we show that VEGF-mediated down-regulation of miR-101 caused pro-angiogenic effects. We found that the pro-angiogenic effects are partly mediated through reduced repression by miR-101 of the histone-methyltransferase EZH2, a member of the Polycomb group family, thereby increasing methylation of histone H3 at lysine 27 and transcriptome alterations. In vitro, the sprouting and migratory properties of primary endothelial cell cultures were reduced by inhibiting EZH2 through up-regulation of miR-101, siRNA-mediated knockdown of EZH2, or treatment with 3-Deazaneplanocin-A (DZNep), a small molecule inhibitor of EZH2 methyltransferase activity. In addition, we found that systemic DZNep administration reduced the number of blood vessels in a subcutaneous glioblastoma mouse model, without showing adverse toxicities. Altogether, by identifying a pro-angiogenic VEGF/miR-101/EZH2 axis in endothelial cells we provide evidence for a functional link between growth factor-mediated signaling, post-transcriptional silencing, and histone-methylation in the angiogenesis process. Inhibition of EZH2 may prove therapeutic in diseases in which aberrant vascularization plays a role.

  • 22. Smits, Michiel
    et al.
    Nilsson, Jonas
    Mir, Shahryar E
    van der Stoop, Petra M
    Hulleman, Esther
    Niers, Johanna M
    de Witt Hamer, Phillip C
    Marquez, Victor E
    Cloos, Jacqueline
    Krichevsky, Anna M
    Noske, David P
    Tannous, Bakhos A
    Würdinger, Thomas
    miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis2010In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 1, no 8, p. 710-720Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Glioblastoma (GBM) is a malignant brain tumor with dismal prognosis. GBM patients have a median survival of less than 2 years. GBM is characterized by fast cell proliferation, infiltrative migration, and by the induction of angiogenesis. MicroRNAs and polycomb group (PcG) proteins have emerged as important regulators of gene expression.

    METHODS: Here we determined that miR-101 is down-regulated in GBM, resulting in overexpression of the miR-101 target PcG protein EZH2, a histone methyltransferase affecting gene expression profiles in an epigenetic manner.

    RESULTS: Inhibition of EZH2 in vitro by pre-miR-101, EZH2 siRNA, or small molecule DZNep, attenuated GBM cell growth, migration/invasion, and GBM-induced endothelial tubule formation. In addition, for each biological process we identified ontology-associated transcripts that significantly correlate with EZH2 expression. Inhibition of EZH2 in vivo by systemic DZNep administration in a U87-Fluc-mCherry GBM xenograft mouse imaging model resulted in reduced tumor growth.

    CONCLUSION: Our results indicate that EZH2 has a versatile function in GBM progression and that its overexpression is at least partly due to decreased miR-101 expression. Inhibition of EZH2 may be a potential therapeutic strategy to target GBM proliferation, migration, and angiogenesis.

  • 23. Tannous, Bakhos A.
    et al.
    Kerami, Mariam
    Van der Stoop, Petra M.
    Kwiatkowski, Nicholas
    Wang, Jinhua
    Zhou, Wenjun
    Kessler, Almuth F.
    Lewandrowski, Grant
    Hiddingh, Lotte
    Sol, Nik
    Lagerweij, Tonny
    Wedekind, Laurine
    Niers, Johanna M.
    Barazas, Marco
    Nilsson, R. Jonas A.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Geerts, Dirk
    Hamer, Philip C. De Witt
    Hagemann, Carsten
    Vandertop, W. Peter
    Van Tellingen, Olaf
    Noske, David P.
    Gray, Nathanael S.
    Wuerdinger, Thomas
    Effects of the Selective MPS1 Inhibitor MPS1-IN-3 on Glioblastoma Sensitivity to Antimitotic Drugs2013In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 105, no 17, p. 1322-1331Article in journal (Refereed)
    Abstract [en]

    Background Glioblastomas exhibit a high level of chemotherapeutic resistance, including to the antimitotic agents vincristine and taxol. During the mitotic agent-induced arrest, glioblastoma cells are able to perform damage-control and self-repair to continue proliferation. Monopolar spindle 1 (MPS1/TTK) is a checkpoint kinase and a gatekeeper of the mitotic arrest.

    Methods We used glioblastoma cells to determine the expression of MPS1 and to determine the effects of MPS1 inhibition on mitotic errors and cell viability in combination with vincristine and taxol. The effect of MPS1 inhibition was assessed in different orthotopic glioblastoma mouse models (n = 3-7 mice/group). MPS1 expression levels were examined in relation to patient survival.

    Results Using publicly available gene expression data, we determined that MPS1 overexpression corresponds positively with tumor grade and negatively with patient survival (two-sided t test, P < .001). Patients with high MPS1 expression (n = 203) had a median and mean survival of 487 and 913 days (95% confidence intervals [CI] = 751 to 1075), respectively, and a 2-year survival rate of 35%, whereas patients with intermediate MPS1 expression (n = 140) had a median and mean survival of 858 and 1183 days (95% CI = 1177 to 1189), respectively, and a 2-year survival rate of 56%. We demonstrate that MPS1 inhibition by RNAi results in sensitization to antimitotic agents. We developed a selective small-molecule inhibitor of MPS1, MPS1-IN-3, which caused mitotic aberrancies in glioblastoma cells and, in combination with vincristine, induced mitotic checkpoint override, increased aneuploidy, and augmented cell death. MPS1-IN-3 sensitizes glioblastoma cells to vincristine in orthotopic mouse models (two-sided log-rank test, P < .01), resulting in prolonged survival without toxicity.

    Conclusions Our results collectively demonstrate that MPS1, a putative therapeutic target in glioblastoma, can be selectively inhibited by MPS1-IN-3 sensitizing glioblastoma cells to antimitotic drugs.

  • 24.
    Tjon-Kon-Fat, Lee-Ann
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Schröder, Mona
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wurdinger, Thomas
    Thellenberg-Karlsson, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nilsson, Rolf Jonas Andreas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Platelets harbor prostate cancer biomarkers and the ability to predict therapeutic response to abiraterone in castration resistant patients2018In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 78, no 1, p. 48-53Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Novel therapies for castration resistant prostate cancer (CRPC) have been introduced in the clinic with possibilities for individualized treatment plans. Best practice of those expensive drugs requires predictive biomarker monitoring. This study used circulating biomarker analysis to follow cancer-derived transcripts implicated in therapy resistance.

    METHOD: The isolated platelet population of blood samples and digital-PCR were used to identify selected biomarker transcripts in patients with CRPC prior chemo- or androgen synthesis inhibiting therapy.

    RESULTS: Fifty patients received either docetaxel (n = 24) or abiraterone (n = 26) therapy, with therapy response rates of 54% and 48%, respectively. Transcripts for the PC-associated biomarkers kallikrein-related peptidase-2 and -3 (KLK2, KLK3), folate hydrolase 1 (FOLH1), and neuropeptide-Y (NPY) were uniquely present within the platelet fraction of cancer patients and not detected in healthy controls (n = 15). In the abiraterone treated cohort, the biomarkers provided information on therapy outcome, demonstrating an association between detectable biomarkers and short progression free survival (PFS) (FOLH1, P < 0.01; KLK3, P < 0.05; and NPY, P < 0.05). Patients with biomarker-negative platelets had the best outcome, while FOLH1 (P < 0.05) and NPY (P = 0.05) biomarkers provided independent predictive information in a multivariate analysis regarding PFS. KLK2 (P < 0.01), KLK3 (P < 0.001), and FOLH1 (P < 0.05) biomarkers were associated with short overall survival (OS). Combining three biomarkers in a panel (KLK3, FOLH1, and NPY) made it possible to separate long-term responders from short-term responders with 87% sensitivity and 82% specificity.

    CONCLUSION: Analyzing tumor-derived biomarkers in platelets of CRPC patients enabled prediction of the outcome after abiraterone therapy with higher accuracy than baseline serum PSA or PSA response.

  • 25.
    Tjon-Kon-Fat, Lee-Ann
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sol, Nik
    Wurdinger, Thomas
    Nilsson, R. Jonas A.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Platelet RNA in Cancer Diagnostics2018In: Seminars in Thrombosis and Hemostasis, ISSN 0094-6176, E-ISSN 1098-9064, Vol. 44, no 2, p. 135-141Article in journal (Refereed)
    Abstract [en]

    Platelets are involved in several steps of cancer metastasis. During this process, platelets are exposed to the tumor and its environment, thereby exchanging biomolecules with the tumor cells and resulting in tumor-mediated education of the platelets and a change in their RNA profile. Analysis of platelet RNA profiles or direct measurement of tumor-derived biomarkers within platelets can provide information on ongoing cancer-related processes in the individual (e.g., whether the patient has cancer, the tumor type, and possibly identify oncogenic alterations driving the disease for treatment selection). The close interaction with the disease process and the ability to respond to systemic alterations make platelets an interesting biosource for implementation in precision medicine.

  • 26. Van Rijn, S.
    et al.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Noske, D. P.
    Peter Vandertop, W.
    Tannous, B. A.
    Würdinger, T.
    Functional multiplex reporter assay using tagged Gaussia luciferase2013In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 3, article id 1046Article in journal (Refereed)
    Abstract [en]

    We have developed a multiplex reporter system to monitor multiple biological variables in real-time. The secreted Gaussia luciferase was fused to ten different epitope tags (Gluc tag), each expressed in different tumor cells. By immunobinding of the tags followed by Gluc tag detection, this system allowed the independent and real-time monitoring of mixed cell cultures in vitro and of mixed subcutaneous and intracranial tumor subpopulations in vivo.

  • 27. van Rijn, Sjoerd
    et al.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Noske, David P.
    Vandertop, W. Peter
    Tannous, Bakhos A.
    Wuerdinger, Thomas
    Transcription Factor Activity Analysis Using a Functional Multiplex Gaussia Luciferase-Based Reporter Assay2013In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 21, p. S123-S124Article in journal (Refereed)
  • 28.
    Yi, Wei
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Holmlund, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Inui, Shigeki
    Department of Regenerative Dermatology, Graduate School of Medicine, Osaka University, Japan.
    Lei, Ting
    Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China.
    Itami, Satoshi
    Department of Regenerative Dermatology, Graduate School of Medicine, Osaka University, Japan.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Paracrine regulation of growth factor signaling by shed leucine-rich repeats and immunoglobulin-like domains 12011In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 317, no 4, p. 504-512Article in journal (Refereed)
    Abstract [en]

    Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a recently discovered negative regulator of growth factor signaling. The LRIG1 integral membrane protein has been demonstrated to regulate various oncogenic receptor tyrosine kinases, including epidermal growth factor (EGF) receptor (EGFR), by cell-autonomous mechanisms. Here, we investigated whether LRIG1 ectodomains were shed, and if LRIG1 could regulate cell proliferation and EGF signaling in a paracrine manner. Cells constitutively shed LRIG1 ectodomains in vitro, and shedding was modulated by known regulators of metalloproteases, including the ADAM17 specific inhibitor TAPI-2. Furthermore, shedding was enhanced by ectopic expression of Adam17. LRIG1 ectodomains appeared to be shed in vivo, as well, as demonstrated by immunoblotting of mouse and human tissue lysates. Ectopic expression of LRIG1 in lymphocytes suppressed EGF signaling in co-cultured fibroblastoid cells, demonstrating that shed LRIG1 ectodomains can function in a paracrine fashion. Purified LRIG1 ectodomains suppressed EGF signaling without any apparent downregulation of EGFR levels. Taken together, the results show that the LRIG1 ectodomain can be proteolytically shed and can function as a non-cell-autonomous regulator of growth factor signaling. Thus, LRIG1 or its ectodomain could have therapeutic potential in the treatment of growth factor receptor-dependent cancers.

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