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1.
Cell Rep Med ; 1(7): 100101, 2020 10 20.
Article in English | MEDLINE | ID: mdl-33103128

ABSTRACT

Tumor-educated platelets (TEPs) are potential biomarkers for cancer diagnostics. We employ TEP-derived RNA panels, determined by swarm intelligence, to detect and monitor glioblastoma. We assessed specificity by comparing the spliced RNA profile of TEPs from glioblastoma patients with multiple sclerosis and brain metastasis patients (validation series, n = 157; accuracy, 80%; AUC, 0.81 [95% CI, 0.74-0.89; p < 0.001]). Second, analysis of patients with glioblastoma versus asymptomatic healthy controls in an independent validation series (n = 347) provided a detection accuracy of 95% and AUC of 0.97 (95% CI, 0.95-0.99; p < 0.001). Finally, we developed the digitalSWARM algorithm to improve monitoring of glioblastoma progression and demonstrate that the TEP tumor scores of individual glioblastoma patients represent tumor behavior and could be used to distinguish false positive progression from true progression (validation series, n = 20; accuracy, 85%; AUC, 0.86 [95% CI, 0.70-1.00; p < 0.012]). In conclusion, TEPs have potential as a minimally invasive biosource for blood-based diagnostics and monitoring of glioblastoma patients.


Subject(s)
Blood Platelets/metabolism , Brain Neoplasms/diagnosis , Glioblastoma/diagnosis , Monitoring, Physiologic/methods , Multiple Sclerosis/diagnosis , RNA, Neoplasm/genetics , Adult , Aged , Aged, 80 and over , Algorithms , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Blood Platelets/pathology , Brain Neoplasms/genetics , Brain Neoplasms/mortality , Brain Neoplasms/surgery , Case-Control Studies , Disease Progression , Glioblastoma/genetics , Glioblastoma/mortality , Glioblastoma/surgery , Humans , Middle Aged , Multiple Sclerosis/genetics , Multiple Sclerosis/pathology , Neoplasm Metastasis , RNA Splicing , RNA, Neoplasm/metabolism , ROC Curve , Survival Analysis , Tumor Microenvironment/genetics
2.
Semin Thromb Hemost ; 44(2): 135-141, 2018 Mar.
Article in English | MEDLINE | ID: mdl-28905353

ABSTRACT

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.


Subject(s)
Blood Platelets/metabolism , Neoplasms/blood , RNA/blood , Humans , Neoplasms/diagnosis
3.
Cancer Cell ; 32(2): 238-252.e9, 2017 08 14.
Article in English | MEDLINE | ID: mdl-28810146

ABSTRACT

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.


Subject(s)
Algorithms , Artificial Intelligence , Blood Platelets/physiology , Carcinoma, Non-Small-Cell Lung/diagnosis , Diagnosis, Computer-Assisted/methods , Lung Neoplasms/diagnosis , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/genetics , Cohort Studies , Female , Gene Expression Profiling , High-Throughput Nucleotide Sequencing , Humans , Inflammation/blood , Inflammation/diagnosis , Inflammation/genetics , Lung Neoplasms/blood , Lung Neoplasms/genetics , Male , Middle Aged , Support Vector Machine
4.
Oncotarget ; 7(13): 16676-87, 2016 Mar 29.
Article in English | MEDLINE | ID: mdl-26918338

ABSTRACT

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.


Subject(s)
Cell Cycle Proteins/biosynthesis , Centrosome/pathology , Gene Expression Regulation, Neoplastic/physiology , MicroRNAs/metabolism , Microtubule-Associated Proteins/biosynthesis , Phosphoproteins/biosynthesis , Prostatic Neoplasms/pathology , Animals , Cell Line, Tumor , Humans , Male , MicroRNAs/genetics , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Rats
5.
Oncotarget ; 7(1): 1066-75, 2016 Jan 05.
Article in English | MEDLINE | ID: mdl-26544515

ABSTRACT

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.


Subject(s)
Blood Platelets/metabolism , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Oncogene Proteins, Fusion/genetics , Pyrazoles/therapeutic use , Pyridines/therapeutic use , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/genetics , Crizotinib , Drug Monitoring/methods , Female , Humans , In Situ Hybridization, Fluorescence , Kaplan-Meier Estimate , Lung Neoplasms/blood , Lung Neoplasms/genetics , Male , Middle Aged , Oncogene Proteins, Fusion/blood , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , Prognosis , Proportional Hazards Models , Protein Kinase Inhibitors/therapeutic use , Reproducibility of Results , Reverse Transcriptase Polymerase Chain Reaction
6.
Cancer Cell ; 28(5): 666-676, 2015 Nov 09.
Article in English | MEDLINE | ID: mdl-26525104

ABSTRACT

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".


Subject(s)
Biomarkers, Tumor/genetics , Blood Platelets/metabolism , Neoplasms/genetics , Signal Transduction/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , Class I Phosphatidylinositol 3-Kinases , ErbB Receptors/genetics , Female , Gene Expression Profiling/methods , Gene Ontology , Humans , Male , Middle Aged , Mutation , Neoplasms/blood , Neoplasms/diagnosis , Pathology, Molecular/methods , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Receptor, ErbB-2/genetics , Reproducibility of Results , Sensitivity and Specificity , Sequence Analysis, RNA/methods , Support Vector Machine , Young Adult
7.
J Natl Cancer Inst ; 105(17): 1322-31, 2013 Sep 04.
Article in English | MEDLINE | ID: mdl-23940287

ABSTRACT

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.


Subject(s)
2-Aminopurine/analogs & derivatives , Antimitotic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Cycle Proteins/antagonists & inhibitors , Glioblastoma/drug therapy , M Phase Cell Cycle Checkpoints/drug effects , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , ortho-Aminobenzoates/pharmacology , 2-Aminopurine/pharmacology , Animals , Antineoplastic Agents, Phytogenic/administration & dosage , Cell Survival/drug effects , Drug Resistance, Neoplasm , France , Frozen Sections , Gene Expression Regulation, Neoplastic , Glioblastoma/mortality , Humans , M Phase Cell Cycle Checkpoints/genetics , Mice , Mice, Nude , Netherlands , Paclitaxel/administration & dosage , RNA Interference/drug effects , United States , Up-Regulation , Vincristine/administration & dosage , Xenograft Model Antitumor Assays
8.
Blood ; 118(13): 3680-3, 2011 Sep 29.
Article in English | MEDLINE | ID: mdl-21832279

ABSTRACT

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.


Subject(s)
Biomarkers, Tumor/metabolism , Blood Platelets/metabolism , Neoplasms/genetics , RNA/metabolism , Animals , Biomarkers, Tumor/analysis , Blood Platelets/chemistry , Brain Neoplasms/blood , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Case-Control Studies , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Genes, Neoplasm , Glioma/blood , Glioma/genetics , Glioma/metabolism , Glioma/pathology , Humans , Male , Mice , Mice, Nude , Microarray Analysis , Neoplasms/metabolism , Prostatic Neoplasms/blood , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , RNA/analysis , RNA/blood , RNA/genetics , Transplantation, Heterologous , Tumor Cells, Cultured
9.
PLoS One ; 6(1): e16282, 2011 Jan 28.
Article in English | MEDLINE | ID: mdl-21297974

ABSTRACT

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.


Subject(s)
DNA-Binding Proteins/biosynthesis , Down-Regulation , Endothelial Cells/physiology , MicroRNAs/genetics , Neovascularization, Physiologic , Transcription Factors/biosynthesis , Angiogenic Proteins/physiology , Animals , Cells, Cultured , DNA-Binding Proteins/genetics , Down-Regulation/genetics , Endothelial Cells/metabolism , Enhancer of Zeste Homolog 2 Protein , Histones/metabolism , Humans , Methylation , Mice , Polycomb Repressive Complex 2 , Transcription Factors/genetics , Vascular Endothelial Growth Factor A/physiology
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