title: Plasma Exosome Profiling of Cancer Patients by a Next Generation Systems Biology Approach.
abstract: Technologies capable of characterizing the full breadth of cellular systems need to be able to measure millions of proteins, isoforms, and complexes simultaneously. We describe an approach that fulfils this criterion: Adaptive Dynamic Artificial Poly-ligand Targeting (ADAPT). ADAPT employs an enriched library of single-stranded oligodeoxynucleotides (ssODNs) to profile complex biological samples, thus achieving an unprecedented coverage of system-wide, native biomolecules. We used ADAPT as a highly specific profiling tool that distinguishes women with or without breast cancer based on circulating exosomes in their blood. To develop ADAPT, we enriched a library of ~1011ssODNs for those associating with exosomes from breast cancer patients or controls. The resulting 106enriched ssODNs were then profiled against plasma from independent groups of healthy and breast cancer-positive women. ssODN-mediated affinity purification and mass spectrometry identified low-abundance exosome-associated proteins and protein complexes, some with known significance in both normal homeostasis and disease. Sequencing of the recovered ssODNs provided quantitative measures that were used to build highly accurate multi-analyte signatures for patient classification. Probing plasma from 500 subjects with a smaller subset of 2000 resynthesized ssODNs stratified healthy, breast biopsy-negative, and -positive women. An AUC of 0.73 was obtained when comparing healthy donors with biopsy-positive patients.
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.
authors.forename: Valeriy
authors.initials: V
authors.lastname: Domenyuk
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Stark
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.
authors.forename: Nianqing
authors.initials: N
authors.lastname: Xiao
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.
authors.forename: Heather A
authors.initials: HA
authors.lastname: O'Neill
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.
authors.forename: Xixi
authors.initials: X
authors.lastname: Wei
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.
authors.forename: Teresa T
authors.initials: TT
authors.lastname: Tinder
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.
authors.forename: Sonal
authors.initials: S
authors.lastname: Tonapi
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Duncan
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.
authors.forename: Tassilo
authors.initials: T
authors.lastname: Hornung
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hunter
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Miglarese
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.
authors.forename: Joachim
authors.initials: J
authors.lastname: Schorr
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Halbert
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Smith 822A, Boston, MA 02215, USA.|Department of Biostatistics, Harvard School of Public Health, 655 Huntington Ave, Boston, MA 0211, USA.
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.affiliation: Complex Adaptive Systems Initiative, Arizona State University, 1475 N. Scottsdale Rd., Suite 361, Scottsdale, AZ 85257, USA.
authors.forename: George
authors.initials: G
authors.lastname: Poste
authors.affiliation: Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Berry
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.|LIMES Program Unit Chemical Biology &Medicinal Chemistry, c/o Kekulé Institut für Organische Chemie und Biochemie, University of Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Mayer
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.|LIMES Program Unit Chemical Biology &Medicinal Chemistry, c/o Kekulé Institut für Organische Chemie und Biochemie, University of Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany.|Chemical Biology Max-Planck-Fellowship Group, Center of Advanced European Studies and Research (CAESAR), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Famulok
authors.affiliation: Caris Life Sciences, 4610 South 44th Place, Phoenix, AZ 85040, USA.
authors.forename: David
authors.initials: D
authors.lastname: Spetzler
mesh_terms: D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D001943:Breast Neoplasms / Q000097:blood* / Q000235:genetics; D055354:Exosomes / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009838:Oligodeoxyribonucleotides / Q000378:metabolism*; D052156:SELEX Aptamer Technique; D017422:Sequence Analysis, DNA; D049490:Systems Biology / Q000379:methods*
chemical_list: D014408:Biomarkers, Tumor; D009838:Oligodeoxyribonucleotides