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1. Detection and localization of early- and late-stage cancers using platelet RNA

Author

Pharmaceutics, Sub Membrane Biochemistry & Biophysics, Afd Pharmaceutics, In ’t Veld, Sjors G.J.G., Arkani, Mohammad, Post, Edward, Antunes-Ferreira, Mafalda, D'Ambrosi, Silvia, Vessies, Daan C.L., Vermunt, Lisa, Vancura, Adrienne, Muller, Mirte, Niemeijer, Anna Larissa N., Tannous, Jihane, Meijer, Laura L., Le Large, Tessa Y.S., Mantini, Giulia, Wondergem, Niels E., Heinhuis, Kimberley M., van Wilpe, Sandra, Smits, A. Josien, Drees, Esther E.E., Roos, Eva, Leurs, Cyra E., Tjon Kon Fat, Lee Ann, van der Lelij, Ewoud J., Dwarshuis, Govert, Kamphuis, Maarten J., Visser, Lisanne E., Harting, Romee, Gregory, Annemijn, Schweiger, Markus W., Wedekind, Laurine E., Ramaker, Jip, Zwaan, Kenn, Verschueren, Heleen, Bahce, Idris, de Langen, Adrianus J., Smit, Egbert F., van den Heuvel, Michel M., Hartemink, Koen J., Kuijpers, Marijke J.E., oude Egbrink, Mirjam G.A., Griffioen, Arjan W., Rossel, Rafael, Hiltermann, T. Jeroen N., Lee-Lewandrowski, Elizabeth, Lewandrowski, Kent B., De Witt Hamer, Philip C., Kouwenhoven, Mathilde, Reijneveld, Jaap C., Leenders, William P.J., Hoeben, Ann, Verdonck-de Leeuw, Irma M., Leemans, C. René, Baatenburg de Jong, Robert J., Terhaard, Chris H.J., Takes, Robert P., Langendijk, Johannes A., de Jager, Saskia C., Kraaijeveld, Adriaan O., Pasterkamp, Gerard, Smits, Minke, Schalken, Jack A., Łapińska-Szumczyk, Sylwia, Łojkowska, Anna, Żaczek, Anna J., Lokhorst, Henk, van de Donk, Niels W.C.J., Nijhof, Inger, Prins, Henk Jan, Zijlstra, Josée M., Idema, Sander, Baayen, Johannes C., Teunissen, Charlotte E., Killestein, Joep, Besselink, Marc G., Brammen, Lindsay, Bachleitner-Hofmann, Thomas, Mateen, Farrah, Plukker, John T.M., Heger, Michal, de Mast, Quirijn, Lisman, Ton, Pegtel, D. Michiel, Bogaard, Harm Jan, Jassem, Jacek, Supernat, Anna, Mehra, Niven, Gerritsen, Winald, de Kroon, Cornelis D., Lok, Christianne A.R., Piek, Jurgen M.J., Steeghs, Neeltje, van Houdt, Winan J., Brakenhoff, Ruud H., Sonke, Gabe S., Verheul, Henk M., Giovannetti, Elisa, Kazemier, Geert, Sabrkhany, Siamack, Schuuring, Ed, Sistermans, Erik A., Wolthuis, Rob, Meijers-Heijboer, Hanne, Dorsman, Josephine, Oudejans, Cees, Ylstra, Bauke, Westerman, Bart A., van den Broek, Daan, Koppers-Lalic, Danijela, Wesseling, Pieter, Nilsson, R. Jonas A., Vandertop, W. Peter, Noske, David P., Tannous, Bakhos A., Sol, Nik, Best, Myron G., Wurdinger, Thomas, Pharmaceutics, Sub Membrane Biochemistry & Biophysics, Afd Pharmaceutics, In ’t Veld, Sjors G.J.G., Arkani, Mohammad, Post, Edward, Antunes-Ferreira, Mafalda, D'Ambrosi, Silvia, Vessies, Daan C.L., Vermunt, Lisa, Vancura, Adrienne, Muller, Mirte, Niemeijer, Anna Larissa N., Tannous, Jihane, Meijer, Laura L., Le Large, Tessa Y.S., Mantini, Giulia, Wondergem, Niels E., Heinhuis, Kimberley M., van Wilpe, Sandra, Smits, A. Josien, Drees, Esther E.E., Roos, Eva, Leurs, Cyra E., Tjon Kon Fat, Lee Ann, van der Lelij, Ewoud J., Dwarshuis, Govert, Kamphuis, Maarten J., Visser, Lisanne E., Harting, Romee, Gregory, Annemijn, Schweiger, Markus W., Wedekind, Laurine E., Ramaker, Jip, Zwaan, Kenn, Verschueren, Heleen, Bahce, Idris, de Langen, Adrianus J., Smit, Egbert F., van den Heuvel, Michel M., Hartemink, Koen J., Kuijpers, Marijke J.E., oude Egbrink, Mirjam G.A., Griffioen, Arjan W., Rossel, Rafael, Hiltermann, T. Jeroen N., Lee-Lewandrowski, Elizabeth, Lewandrowski, Kent B., De Witt Hamer, Philip C., Kouwenhoven, Mathilde, Reijneveld, Jaap C., Leenders, William P.J., Hoeben, Ann, Verdonck-de Leeuw, Irma M., Leemans, C. René, Baatenburg de Jong, Robert J., Terhaard, Chris H.J., Takes, Robert P., Langendijk, Johannes A., de Jager, Saskia C., Kraaijeveld, Adriaan O., Pasterkamp, Gerard, Smits, Minke, Schalken, Jack A., Łapińska-Szumczyk, Sylwia, Łojkowska, Anna, Żaczek, Anna J., Lokhorst, Henk, van de Donk, Niels W.C.J., Nijhof, Inger, Prins, Henk Jan, Zijlstra, Josée M., Idema, Sander, Baayen, Johannes C., Teunissen, Charlotte E., Killestein, Joep, Besselink, Marc G., Brammen, Lindsay, Bachleitner-Hofmann, Thomas, Mateen, Farrah, Plukker, John T.M., Heger, Michal, de Mast, Quirijn, Lisman, Ton, Pegtel, D. Michiel, Bogaard, Harm Jan, Jassem, Jacek, Supernat, Anna, Mehra, Niven, Gerritsen, Winald, de Kroon, Cornelis D., Lok, Christianne A.R., Piek, Jurgen M.J., Steeghs, Neeltje, van Houdt, Winan J., Brakenhoff, Ruud H., Sonke, Gabe S., Verheul, Henk M., Giovannetti, Elisa, Kazemier, Geert, Sabrkhany, Siamack, Schuuring, Ed, Sistermans, Erik A., Wolthuis, Rob, Meijers-Heijboer, Hanne, Dorsman, Josephine, Oudejans, Cees, Ylstra, Bauke, Westerman, Bart A., van den Broek, Daan, Koppers-Lalic, Danijela, Wesseling, Pieter, Nilsson, R. Jonas A., Vandertop, W. Peter, Noske, David P., Tannous, Bakhos A., Sol, Nik, Best, Myron G., and Wurdinger, Thomas

Published
2022

2. Detection and localization of early- and late-stage cancers using platelet RNA.

Author

In 't Veld SGJG, Arkani M, Post E, Antunes-Ferreira M, D'Ambrosi S, Vessies DCL, Vermunt L, Vancura A, Muller M, Niemeijer AN, Tannous J, Meijer LL, Le Large TYS, Mantini G, Wondergem NE, Heinhuis KM, van Wilpe S, Smits AJ, Drees EEE, Roos E, Leurs CE, Tjon Kon Fat LA, van der Lelij EJ, Dwarshuis G, Kamphuis MJ, Visser LE, Harting R, Gregory A, Schweiger MW, Wedekind LE, Ramaker J, Zwaan K, Verschueren H, Bahce I, de Langen AJ, Smit EF, van den Heuvel MM, Hartemink KJ, Kuijpers MJE, Oude Egbrink MGA, Griffioen AW, Rossel R, Hiltermann TJN, Lee-Lewandrowski E, Lewandrowski KB, De Witt Hamer PC, Kouwenhoven M, Reijneveld JC, Leenders WPJ, Hoeben A, Verdonck-de Leeuw IM, Leemans CR, Baatenburg de Jong RJ, Terhaard CHJ, Takes RP, Langendijk JA, de Jager SC, Kraaijeveld AO, Pasterkamp G, Smits M, Schalken JA, Łapińska-Szumczyk S, Łojkowska A, Żaczek AJ, Lokhorst H, van de Donk NWCJ, Nijhof I, Prins HJ, Zijlstra JM, Idema S, Baayen JC, Teunissen CE, Killestein J, Besselink MG, Brammen L, Bachleitner-Hofmann T, Mateen F, Plukker JTM, Heger M, de Mast Q, Lisman T, Pegtel DM, Bogaard HJ, Jassem J, Supernat A, Mehra N, Gerritsen W, de Kroon CD, Lok CAR, Piek JMJ, Steeghs N, van Houdt WJ, Brakenhoff RH, Sonke GS, Verheul HM, Giovannetti E, Kazemier G, Sabrkhany S, Schuuring E, Sistermans EA, Wolthuis R, Meijers-Heijboer H, Dorsman J, Oudejans C, Ylstra B, Westerman BA, van den Broek D, Koppers-Lalic D, Wesseling P, Nilsson RJA, Vandertop WP, Noske DP, Tannous BA, Sol N, Best MG, and Wurdinger T

Subjects
Biomarkers, Tumor genetics, Blood Platelets, Early Detection of Cancer methods, Humans, Neoplasms diagnosis, Neoplasms genetics, RNA genetics
Abstract

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening., Competing Interests: Declaration of interests M.G. Best, R.J.A.N., and T.W. are inventors on relevant patent applications (PCT/NL2011/050518 and PCT/NL2018/050110). R.J.A.N. and T.W. are shareholders of Illumina, Inc. M.H. is chief formulation officer at Nurish.Me, Inc., and Camelina Sun LLC and has equity in those companies (whose business activities are unrelated to the present work). D.M.P. and D.K.L. are shareholders of ExBiome BV., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2022
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3. iPSC-Based Modeling of RAG2 Severe Combined Immunodeficiency Reveals Multiple T Cell Developmental Arrests.

Author

Themeli M, Chhatta A, Boersma H, Prins HJ, Cordes M, de Wilt E, Farahani AS, Vandekerckhove B, van der Burg M, Hoeben RC, Staal FJT, and Mikkers HMM

Subjects
Animals, Antigens, CD metabolism, Cell Differentiation, Cell Lineage, Gene Rearrangement, beta-Chain T-Cell Antigen Receptor, Hematopoiesis, Humans, Killer Cells, Natural immunology, Mice, SCID, DNA-Binding Proteins metabolism, Induced Pluripotent Stem Cells metabolism, Models, Biological, Severe Combined Immunodeficiency immunology, Severe Combined Immunodeficiency pathology, T-Lymphocytes immunology
Abstract

RAG2 severe combined immune deficiency (RAG2-SCID) is a lethal disorder caused by the absence of functional T and B cells due to a differentiation block. Here, we generated induced pluripotent stem cells (iPSCs) from a RAG2-SCID patient to study the nature of the T cell developmental blockade. We observed a strongly reduced capacity to differentiate at every investigated stage of T cell development, from early CD7 - CD5 - to CD4 + CD8 + . The impaired differentiation was accompanied by an increase in CD7 - CD56 + CD33 + natural killer (NK) cell-like cells. T cell receptor D rearrangements were completely absent in RAG2SCID cells, whereas the rare T cell receptor B rearrangements were likely the result of illegitimate rearrangements. Repair of RAG2 restored the capacity to induce T cell receptor rearrangements, normalized T cell development, and corrected the NK cell-like phenotype. In conclusion, we succeeded in generating an iPSC-based RAG2-SCID model, which enabled the identification of previously unrecognized disorder-related T cell developmental roadblocks., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2020
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4. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids.

Author

Roodhart JM, Daenen LG, Stigter EC, Prins HJ, Gerrits J, Houthuijzen JM, Gerritsen MG, Schipper HS, Backer MJ, van Amersfoort M, Vermaat JS, Moerer P, Ishihara K, Kalkhoven E, Beijnen JH, Derksen PW, Medema RH, Martens AC, Brenkman AB, and Voest EE

Subjects
Animals, Apoptosis drug effects, Carboplatin administration & dosage, Carboplatin pharmacology, Cisplatin administration & dosage, Cisplatin pharmacology, Cyclooxygenase Inhibitors, Humans, Mass Spectrometry, Metabolomics, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Organoplatinum Compounds administration & dosage, Organoplatinum Compounds pharmacology, Oxaliplatin, Thromboxane-A Synthase antagonists & inhibitors, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Cyclooxygenase 1 metabolism, Drug Resistance, Neoplasm, Fatty Acids metabolism, Fatty Acids, Unsaturated metabolism, Mesenchymal Stem Cells metabolism, Platinum Compounds pharmacology, Thromboxane-A Synthase metabolism
Abstract

The development of resistance to chemotherapy is a major obstacle for lasting effective treatment of cancer. Here, we demonstrate that endogenous mesenchymal stem cells (MSCs) become activated during treatment with platinum analogs and secrete factors that protect tumor cells against a range of chemotherapeutics. Through a metabolomics approach, we identified two distinct platinum-induced polyunsaturated fatty acids (PIFAs), 12-oxo-5,8,10-heptadecatrienoic acid (KHT) and hexadeca-4,7,10,13-tetraenoic acid (16:4(n-3)), that in minute quantities induce resistance to a broad spectrum of chemotherapeutic agents. Interestingly, blocking central enzymes involved in the production of these PIFAs (cyclooxygenase-1 and thromboxane synthase) prevents MSC-induced resistance. Our findings show that MSCs are potent mediators of resistance to chemotherapy and reveal targets to enhance chemotherapy efficacy in patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Published
2011
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