(1) Siegel, R. L.; Miller, K. D.; Jemal, A. Cancer statistics, 2020. CaCancer J. Clin. 2020, 70, 7−30.
(2) Ostrom, Q. T.; Patil, N.; Cioffi, G.; Waite, K.; Kruchko, C.;
Barnholtz-Sloan, J. S. CBTRUS Statistical Report: Primary Brain and
Other Central Nervous System Tumors Diagnosed in the United
States in 2013-2017. Neuro-Oncology 2020, 22, iv1−iv96.
(3) Best, M. G.; Sol, N.; Zijl, S.; Reijneveld, J. C.; Wesseling, P.;
Wurdinger, T. Liquid biopsies in patients with diffuse glioma. Acta
Neuropathol. 2015, 129, 849−865.
(4) Heitzer, E.; Perakis, S.; Geigl, J. B.; Speicher, M. R. The potential
of liquid biopsies for the early detection of cancer. npj Precis. Oncol.
2017, 1, No. 36.
(5) Bartel, D. P. MicroRNAs- Genomics, Biogenesis, Mechanism,
and Function. Cell 2004, 116, 281−297.
(6) Valadi, H.; Ekstrom, K.; Bossios, A.; Sjostrand, M.; Lee, J. J.;
Lotvall, J. O. Exosome-mediated transfer of mRNAs and microRNAs
is a novel mechanism of genetic exchange between cells. Nat. Cell Biol.
2007, 9, 654−659.
(7) Pegtel, D. M.; Cosmopoulos, K.; Thorley-Lawson, D. A.; van
Eijndhoven, M. A.; Hopmans, E. S.; Lindenberg, J. L.; de Gruijl, T. D.;
Wurdinger, T.; Middeldorp, J. M. Functional delivery of viral miRNAs
via exosomes. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 6328−6333.
(8) Shimomura, A.; Shiino, S.; Kawauchi, J.; Takizawa, S.; Sakamoto,
H.; Matsuzaki, J.; Ono, M.; Takeshita, F.; Niida, S.; Shimizu, C.;
Fujiwara, Y.; Kinoshita, T.; Tamura, K.; Ochiya, T. Novel
combination of serum microRNA for detecting breast cancer in the
early stage. Cancer Sci. 2016, 107, 326−334.
(9) Yokoi, A.; Matsuzaki, J.; Yamamoto, Y.; Yoneoka, Y.; Takahashi,
K.; Shimizu, H.; Uehara, T.; Ishikawa, M.; Ikeda, S. I.; Sonoda, T.;
Kawauchi, J.; Takizawa, S.; Aoki, Y.; Niida, S.; Sakamoto, H.; Kato,
K.; Kato, T.; Ochiya, T. Integrated extracellular microRNA profiling
for ovarian cancer screening. Nat. Commun. 2018, 9, No. 4319.
(10) Usuba, W.; Urabe, F.; Yamamoto, Y.; Matsuzaki, J.; Sasaki, H.;
Ichikawa, M.; Takizawa, S.; Aoki, Y.; Niida, S.; Kato, K.; Egawa, S.;
Chikaraishi, T.; Fujimoto, H.; Ochiya, T. Circulating miRNA panels
for specific and early detection in bladder cancer. Cancer Sci. 2019,
110, 408−419.
(11) Kim, H.; Park, S.; Jeong, I. G.; Song, S. H.; Jeong, Y.; Kim, C.
S.; Lee, K. H. Noninvasive Precision Screening of Prostate Cancer by
Urinary Multimarker Sensor and Artificial Intelligence Analysis. ACS
Nano 2021, 15, 4054−4065.
(12) Cheng, L.; Sun, X.; Scicluna, B. J.; Coleman, B. M.; Hill, A. F.
Characterization and deep sequencing analysis of exosomal and nonexosomal miRNA in human urine. Kidney Int. 2014, 86, 433−444.
(13) Sun, J.; Han, S.; Ma, L.; Zhang, H.; Zhan, Z.; Aguilar, H. A.;
Zhang, H.; Xiao, K.; Gu, Y.; Gu, Z.; Tao, W. A. Synergistically
Bifunctional Paramagnetic Separation Enables Efficient Isolation of
Urine Extracellular Vesicles and Downstream Phosphoproteomic
Analysis. ACS Appl. Mater. Interfaces 2021, 13, 3622−3630.
(14) Yasui, T.; Yanagida, T.; Ito, S.; Konakade, Y.; Takeshita, T.;
Naganawa, T.; Nagashima, K.; Shimada, T.; Kaji, N.; Nakamura, Y.;
Thiodorus, A. I.; He, Y.; Rahong, S.; Kanai, M.; Yukawa, H.; Ochiya,
T.; Kawai, T.; Baba, Y. Unveiling massive numbers of cancer-related
urinary-microRNA candidates via nanowires. Sci. Adv. 2017, 3,
No. e1701133.
(15) Abbott, N. J.; Patabendige, A. A.; Dolman, D. E.; Yusof, S. R.;
Begley, D. J. Structure and function of the blood-brain barrier.
Neurobiol. Dis. 2010, 37, 13−25.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Chemistry for Multimolecular
Crowding Biosystems” (JSPS KAKENHI Grant no. 17H06356
to A.N.), a PRESTO (JST Grant no. JPMJPR19H9 to T.Y.), a
Medical Research and Development Program (AMED Grand
no. JP21he2302007 to T.Y. and A.N.), a SICORP (JST Grant
no. JPMJSC19E3 to T.Y.), a Grant-in-Aid for Young Scientists
(A) (JSPS KAKENHI Grant no. 17H04803 to T.Y.), a Grantin-Aid for Scientific Research (S) (JSPS KAKENHI Grant no.
18H05243 to T.Y.), a Grant-in-Aid for Exploratory Research
(JSPS KAKENHI Grant no. 20K21124 to T.Y.), and a Grantin-Aid for Young Scientists (B) (JSPS KAKENHI Grant no.
17K16643 to K.A.).
ABBREVIATIONS
AUC, area under the curve
BBB, blood−brain barrier
CI, confidence interval
CNS, central nervous system
COP, cyclo-olefin polymer
CT, computed tomography
DEM, differentially expressed microRNA
DNT, dysembryoplastic neuroepithelial tumor
EV, extracellular vesicle
FBS, fetal bovine serum
GBM, glioblastoma
GBO, glioblastoma organoid
GEO, Gene Expression Omnibus
GO, Gene Ontology
IDH, isocitrate dehydrogenase
IHC, immunohistochemistry
LASSO, least absolute shrinkage and selection operator
LGG, lower grade glioma
mRNA, messenger RNAs
miRNA, microRNA
MRI, magnetic resonance imaging
MVNT, multinodular and vacuolating neuronal tumor of
the cerebrum
N/A, not applicable
NCBI, National Center for Biotechnology Information
NHA, normal human astrocyte
NOS, not otherwise specified
nt, nucleotide
PBS, phosphate-buffered saline
PCR, polymerase chain reaction
PDMS, poly(dimethylsiloxane)
PEEK, polyether ether ketone
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(16) Jacob, F.; Salinas, R. D.; Zhang, D. Y.; Nguyen, P. T. T.;
Schnoll, J. G.; Wong, S. Z. H.; Thokala, R.; Sheikh, S.; Saxena, D.;
Prokop, S.; Liu, D. A.; Qian, X.; Petrov, D.; Lucas, T.; Chen, H. I.;
Dorsey, J. F.; Christian, K. M.; Binder, Z. A.; Nasrallah, M.; Brem, S.;
OʼRourke, D. M.; Ming, G. L.; Song, H. A Patient-Derived
Glioblastoma Organoid Model and Biobank Recapitulates Interand Intra-tumoral Heterogeneity. Cell 2020, 180, 188−204.
(17) Golebiewska, A.; Hau, A. C.; Oudin, A.; Stieber, D.; Yabo, Y.
A.; Baus, V.; Barthelemy, V.; Klein, E.; Bougnaud, S.; Keunen, O.;
Wantz, M.; Michelucci, A.; Neirinckx, V.; Muller, A.; Kaoma, T.;
Nazarov, P. V.; Azuaje, F.; De Falco, A.; Flies, B.; Richart, L.;
Poovathingal, S.; Arns, T.; Grzyb, K.; Mock, A.; Herold-Mende, C.;
Steino, A.; Brown, D.; May, P.; Miletic, H.; Malta, T. M.; Noushmehr,
H.; Kwon, Y. J.; Jahn, W.; Klink, B.; Tanner, G.; Stead, L. F.;
Mittelbronn, M.; Skupin, A.; Hertel, F.; Bjerkvig, R.; Niclou, S. P.
Patient-derived organoids and orthotopic xenografts of primary and
recurrent gliomas represent relevant patient avatars for precision
oncology. Acta Neuropathol. 2020, 140, 919−949.
(18) Szvicsek, Z.; Oszvald, A.; Szabo, L.; Sandor, G. O.; Kelemen,
A.; Soos, A. A.; Paloczi, K.; Harsanyi, L.; Tolgyes, T.; Dede, K.;
Bursics, A.; Buzas, E. I.; Zeold, A.; Wiener, Z. Extracellular vesicle
release from intestinal organoids is modulated by Apc mutation and
other colorectal cancer progression factors. Cell. Mol. Life Sci. 2019,
76, 2463−2476.
(19) Shinohara, H.; Yagita, H.; Ikawa, Y.; Oyaizu, N. Fas Drives Cell
Cycle Progression in Glioma Cells Via Extracellular Signal- Regulated
Kinase Activation. Cancer Res. 2000, 60, 1766−1772.
(20) Pulvirenti, T.; Van Der Heijden, M.; Droms, L. A.; Huse, J. T.;
Tabar, V.; Hall, A. Dishevelled 2 signaling promotes self-renewal and
tumorigenicity in human gliomas. Cancer Res. 2011, 71, 7280−7290.
(21) Obuchowski, N. A.; Bullen, J. A. Receiver operating
characteristic (ROC) curves: review of methods with applications in
diagnostic medicine. Phys. Med. Biol. 2018, 63, No. 07TR01.
(22) Fluss, R.; Faraggi, D.; Reiser, B. Estimation of the Youden
Index and its associated cutoff point. Biom. J. 2005, 47, 458−472.
(23) Hoo, Z. H.; Candlish, J.; Teare, D. What is an ROC curve?
Emerg. Med. J. 2017, 34, 357−359.
(24) Song, P.; Ye, D.; Zuo, X.; Li, J.; Wang, J.; Liu, H.; Hwang, M.
T.; Chao, J.; Su, S.; Wang, L.; Shi, J.; Wang, L.; Huang, W.; Lal, R.;
Fan, C. DNA Hydrogel with Aptamer-Toehold-Based Recognition,
Cloaking, and Decloaking of Circulating Tumor Cells for Live Cell
Analysis. Nano Lett. 2017, 17, 5193−5198.
(25) Dong, S.; Wang, Y.; Liu, Z.; Zhang, W.; Yi, K.; Zhang, X.;
Zhang, X.; Jiang, C.; Yang, S.; Wang, F.; Xiao, X. Beehive-Inspired
Macroporous SERS Probe for Cancer Detection through Capturing
and Analyzing Exosomes in Plasma. ACS Appl. Mater. Interfaces 2020,
12, 5136−5146.
(26) Smith, R.; Duan, W.; Quarterman, J.; Morris, A.; Collie, C.;
Black, M.; Toor, F.; Salem, A. K. Surface Modifying Doped Silicon
Nanowire Based Solar Cells for Applications in Biosensing. Adv.
Mater. Technol. 2019, 4, No. 1800349.
(27) Morad, G.; Carman, C. V.; Hagedorn, E. J.; Perlin, J. R.; Zon, L.
I.; Mustafaoglu, N.; Park, T. E.; Ingber, D. E.; Daisy, C. C.; Moses, M.
A. Tumor-Derived Extracellular Vesicles Breach the Intact BloodBrain Barrier via Transcytosis. ACS Nano 2019, 13, 13853−13865.
(28) Suzuki, H.; Aoki, K.; Chiba, K.; Sato, Y.; Shiozawa, Y.; Shiraishi,
Y.; Shimamura, T.; Niida, A.; Motomura, K.; Ohka, F.; Yamamoto, T.;
Tanahashi, K.; Ranjit, M.; Wakabayashi, T.; Yoshizato, T.; Kataoka,
K.; Yoshida, K.; Nagata, Y.; Sato-Otsubo, A.; Tanaka, H.; Sanada, M.;
Kondo, Y.; Nakamura, H.; Mizoguchi, M.; Abe, T.; Muragaki, Y.;
Watanabe, R.; Ito, I.; Miyano, S.; Natsume, A.; Ogawa, S. Mutational
landscape and clonal architecture in grade II and III gliomas. Nat.
Genet. 2015, 47, 458−468.
(29) Aoki, K.; Nakamura, H.; Suzuki, H.; Matsuo, K.; Kataoka, K.;
Shimamura, T.; Motomura, K.; Ohka, F.; Shiina, S.; Yamamoto, T.;
Nagata, Y.; Yoshizato, T.; Mizoguchi, M.; Abe, T.; Momii, Y.;
Muragaki, Y.; Watanabe, R.; Ito, I.; Sanada, M.; Yajima, H.; Morita,
N.; Takeuchi, I.; Miyano, S.; Wakabayashi, T.; Ogawa, S.; Natsume,
A. Prognostic relevance of genetic alterations in diffuse lower-grade
gliomas. Neuro-Oncololgy 2018, 20, 66−77.
(30) Ellingson, B. M.; Abrey, L. E.; Nelson, S. J.; Kaufmann, T. J.;
Garcia, J.; Chinot, O.; Saran, F.; Nishikawa, R.; Henriksson, R.;
Mason, W. P.; Wick, W.; Butowski, N.; Ligon, K. L.; Gerstner, E. R.;
Colman, H.; de Groot, J.; Chang, S.; Mellinghoff, I.; Young, R. J.;
Alexander, B. M.; Colen, R.; Taylor, J. W.; Arrillaga-Romany, I.;
Mehta, A.; Huang, R. Y.; Pope, W. B.; Reardon, D.; Batchelor, T.;
Prados, M.; Galanis, E.; Wen, P. Y.; Cloughesy, T. F. Validation of
postoperative residual contrast-enhancing tumor volume as an
independent prognostic factor for overall survival in newly diagnosed
glioblastoma. Neuro-Oncology 2018, 20, 1240−1250.
(31) Zachariah, M. A.; Oliveira-Costa, J. P.; Carter, B. S.; Stott, S. L.;
Nahed, B. V. Blood-based biomarkers for the diagnosis and
monitoring of gliomas. Neuro-Oncology 2018, 20, 1155−1161.
(32) Ohno, M.; Matsuzaki, J.; Kawauchi, J.; Aoki, Y.; Miura, J.;
Takizawa, S.; Kato, K.; Sakamoto, H.; Matsushita, Y.; Takahashi, M.;
Miyakita, Y.; Ichimura, K.; Narita, Y.; Ochiya, T. Assessment of the
Diagnostic Utility of Serum MicroRNA Classification in Patients With
Diffuse Glioma. JAMA Netw. Open 2019, 2, No. e1916953.
(33) Ledur, P. F.; Onzi, G. R.; Zong, H.; Lenz, G. Culture
Conditions Defining Glioblastoma Cells Behavior: What Is the
Impact for Novel Discoveries? Oncotarget 2017, 8, 69185−69197.
(34) Schalper, K. A.; Rodriguez-Ruiz, M. E.; Diez-Valle, R.; LopezJaneiro, A.; Porciuncula, A.; Idoate, M. A.; Inoges, S.; de Andrea, C.;
Lopez-Diaz de Cerio, A.; Tejada, S.; Berraondo, P.; VillarroelEspindola, F.; Choi, J.; Gurpide, A.; Giraldez, M.; Goicoechea, I.;
Gallego Perez-Larraya, J.; Sanmamed, M. F.; Perez-Gracia, J. L.;
Melero, I. Neoadjuvant nivolumab modifies the tumor immune
microenvironment in resectable glioblastoma. Nat. Med. 2019, 25,
470−476.
(35) Cloughesy, T. F.; Mochizuki, A. Y.; Orpilla, J. R.; Hugo, W.;
Lee, A. H.; Davidson, T. B.; Wang, A. C.; Ellingson, B. M.; Rytlewski,
J. A.; Sanders, C. M.; Kawaguchi, E. S.; Du, L.; Li, G.; Yong, W. H.;
Gaffey, S. C.; Cohen, A. L.; Mellinghoff, I. K.; Lee, E. Q.; Reardon, D.
A.; OʼBrien, B. J.; Butowski, N. A.; Nghiemphu, P. L.; Clarke, J. L.;
Arrillaga-Romany, I. C.; Colman, H.; Kaley, T. J.; de Groot, J. F.; Liau,
L. M.; Wen, P. Y.; Prins, R. M. Neoadjuvant anti-PD-1
immunotherapy promotes a survival benefit with intratumoral and
systemic immune responses in recurrent glioblastoma. Nat. Med.
2019, 25, 477−486.
(36) Jeppesen, D. K.; Hvam, M. L.; Primdahl-Bengtson, B.; Boysen,
A. T.; Whitehead, B.; Dyrskjot, L.; Orntoft, T. F.; Howard, K. A.;
Ostenfeld, M. S. Comparative analysis of discrete exosome fractions
obtained by differential centrifugation. J. Extracell. Vesicles 2014, 3,
No. 25011.
(37) Hirano, M.; Ohka, F.; Maeda, S.; Chalise, L.; Yamamichi, A.;
Aoki, K.; Kato, A.; Tanahashi, K.; Motomura, K.; Nishimura, Y.; Hara,
M.; Shinjo, K.; Kondo, Y.; Wakabayashi, T.; Natsume, A. A novel
high-sensitivity assay to detect a small fraction of mutant IDH1 using
droplet digital PCR. Brain Tumor Pathol. 2018, 35, 97−105.
(38) Louis, D. N.; Perry, A.; Reifenberger, G.; von Deimling, A.;
Figarella-Branger, D.; Cavenee, W. K.; Ohgaki, H.; Wiestler, O. D.;
Kleihues, P.; Ellison, D. W. The 2016 World Health Organization
Classification of Tumors of the Central Nervous System: a summary.
Acta Neuropathol. 2016, 131, 803−820.
(39) Li, H.; Durbin, R. Fast and accurate short read alignment with
Burrows-Wheeler transform. Bioinformatics 2009, 25, 1754−1760.
(40) Cibulskis, K.; Lawrence, M. S.; Carter, S. L.; Sivachenko, A.;
Jaffe, D.; Sougnez, C.; Gabriel, S.; Meyerson, M.; Lander, E. S.; Getz,
G. Sensitive detection of somatic point mutations in impure and
heterogeneous cancer samples. Nat. Biotechnol. 2013, 31, 213−219.
(41) Yokoi, A.; Yoshioka, Y.; Hirakawa, A.; Yamamoto, Y.; Ishikawa,
M.; Ikeda, S.; Kato, T.; Niimi, K.; Kajiyama, H.; Kikkawa, F.; Ochiya,
T. A Combination of Circulating Mirnas for the Early Detection of
Ovarian Cancer. Oncotarget 2017, 8, 89811−89823.
(42) Sonoda, Y.; Ozawa, T.; Hirose, Y.; Aldape, D. K.; McMahon,
M.; Berger, S. M.; Pieper, O. R. Formation of Intracranial Tumors by
Genetically Modified Human Astrocytes Defines Four Pathways
17328
Research Article
https://doi.org/10.1021/acsami.1c01754
ACS Appl. Mater. Interfaces 2021, 13, 17316−17329
ACS Applied Materials & Interfaces
www.acsami.org
Research Article
Critical in the Development of Human Anaplastic Astrocytoma.
Cancer Res. 2001, 61, 4956−4960.
(43) Ohka, F.; Shinjo, K.; Deguchi, S.; Matsui, Y.; Okuno, Y.;
Katsushima, K.; Suzuki, M.; Kato, A.; Ogiso, N.; Yamamichi, A.; Aoki,
K.; Suzuki, H.; Sato, S.; Arul Rayan, N.; Prabhakar, S.; Goke, J.;
Shimamura, T.; Maruyama, R.; Takahashi, S.; Suzumura, A.; Kimura,
H.; Wakabayashi, T.; Zong, H.; Natsume, A.; Kondo, Y. Pathogenic
Epigenetic Consequences of Genetic Alterations in IDH-Wild-Type
Diffuse Astrocytic Gliomas. Cancer Res. 2019, 79, 4814−4827.
(44) Takahashi, I.; Hama, Y.; Matsushima, M.; Hirotani, M.; Kano,
T.; Hohzen, H.; Yabe, I.; Utsumi, J.; Sasaki, H. Identification of
plasma microRNAs as a biomarker of sporadic Amyotrophic Lateral
Sclerosis. Mol. Brain 2015, 8, No. 67.
(45) Duan, J.; Soussen, C.; Brie, D.; Idier, J.; Wan, M.; Wang, Y. P.
Generalized LASSO with under-determined regularization matrices.
Signal Process. 2016, 127, 239−246.
(46) Li, J. H.; Liu, S.; Zhou, H.; Qu, L. H.; Yang, J. H. starBase v2.0:
decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res.
2014, 42, D92−D97.
(47) Deguchi, S.; Katsushima, K.; Hatanaka, A.; Shinjo, K.; Ohka, F.;
Wakabayashi, T.; Zong, H.; Natsume, A.; Kondo, Y. Oncogenic
effects of evolutionarily conserved noncoding RNA ECONEXIN on
gliomagenesis. Oncogene 2017, 36, 4629−4640.
(48) Ranjit, M.; Hirano, M.; Aoki, K.; Okuno, Y.; Ohka, F.;
Yamamichi, A.; Kato, A.; Maeda, S.; Motomura, K.; Matsuo, K.;
Enomoto, A.; Ino, Y.; Todo, T.; Takahashi, M.; Wakabayashi, T.;
Kato, T.; Natsume, A. Aberrant Active cis-Regulatory Elements
Associated with Downregulation of RET Finger Protein Overcome
Chemoresistance in Glioblastoma. Cell Rep. 2019, 26, 2274−2281.
(49) Benjamini, Y.; Hochberg, Y. Controlling the False Discovery
Rate: A Practical and Powerful Approach to Multiple Testing. J. R.
Stat. Soc. 1995, 57, 289−300.
17329
https://doi.org/10.1021/acsami.1c01754
ACS Appl. Mater. Interfaces 2021, 13, 17316−17329
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