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  • 1. 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.

  • 2.
    Tjon-Kon-Fat, Lee-Ann
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Circulating platelets: a novel liquid biopsy source for cancer diagnostics and therapy stratification2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    As conventional tissue biopsies have several drawbacks, much effort has been directed toward the development of minimal-invasive liquid biopsy platforms for detecting and profiling cancer.

    Platelets are the second most abundant cells in blood and have very versatile functions both in physiological and pathophysiological conditions. When exposed to tumors and their environment, platelets exchange biomolecules with tumor cells changing the platelets’ RNA profile, resulting in tumor-mediated education of the platelets. Our research group and collaborators have previously shown that platelets sequester material while in circulation and with that ability accumulate cancer specific information. Platelet RNA profiles or detection of tumor-derived biomarkers within them may provide insight into ongoing cancer-related processes in a patient, allowing for implementation of personalized therapy strategies.

    This thesis evaluates whether circulating platelets could have a potential role (as a liquid biopsy source) in cancer diagnostics, therapy stratification, and monitoring of the disease. Gene expression analysis using digital droplet PCR and RNA-sequencing were the main methods used to address this. Prostate Cancer is the main model used in this thesis but this platform is applicable to other tumor types such as colorectal-, breast-, and lung cancer.

    We found platelets of cancer patients to contain tumor-derived information enabling selection of biomarker panels discriminating early stage cancer patients from healthy individuals as well as therapy responders from non-responders with high accuracy. The RNA transcript within the platelets was more informative in regards to therapy stratification compared to circulating free DNA of matched patient samples, in which genomic changes were analyzed. Combining both increased the accuracy in predicting therapy outcome.

    Platelets show usefulness as a novel liquid biopsy source for early detection and individualizing patient therapy decisions (for personalized medicine). The techniques used are promising but large-scale validation is necessary.

  • 3.
    Tjon-Kon-Fat, Lee-Ann
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Köhn, Linda
    Best, Myron
    In't Velt, Sjors
    Lundholm, Marie
    Thellenberg-Karlsson, Camilla
    Widmark, Anders
    Berg, Anders
    Wurdinger, Thomas
    Wikström, Pernilla
    Nilsson, Jonas
    Detection of Early Stage Prostate Cancer Using Tumor Educated Platelet Profile Support Vector Machine (SVM) - Classification AlgorithmsManuscript (preprint) (Other academic)
  • 4.
    Tjon-Kon-Fat, Lee-Ann
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Köhn, Linda
    Lundholm, Marie
    Wurdinger, Thomas
    Thellenberg-Karlsson, Camilla
    Widmark, Anders
    Wikström, Pernilla
    Nilsson, Jonas
    Combining Circulating Biomarkers to Enhance Predictability of Therapy ResponseManuscript (preprint) (Other academic)
  • 5.
    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.

  • 6.
    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.

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