title: Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways.
abstract: Cancer dormancy refers to the prolonged clinical disease-free time between removal of the primary tumor and recurrence, which is common in prostate cancer (PCa), breast cancer, esophageal cancer, and other cancers. PCa disseminated tumor cells (DTC) are detected in both patients with no evidence of disease (NED) and advanced disease (ADV). However, the molecular and cellular nature of DTC is unknown. We performed a first-in-field study of single DTC transcriptomic analyses in cancer patients to identify a molecular signature associated with cancer dormancy. We profiled eighty-five individual EpCAM⁺/CD45⁻ cells from the bone marrow of PCa patients with NED or ADV. We analyzed 44 DTC with high prostate-epithelial signatures, and eliminated 41 cells with high erythroid signatures and low prostate epithelial signatures. DTC were clustered into 3 groups: NED, ADV_1, and ADV_2, in which the ADV_1 group presented a distinct gene expression pattern associated with the p38 stress activated kinase pathway. Additionally, DTC from the NED group were enriched for a tumor dormancy signature associated with head and neck squamous carcinoma and breast cancer. This study provides the first clinical evidence of the p38 pathway as a potential biomarker for early recurrence and an attractive target for therapeutic intervention.
authors.affiliation: Department of Urology, University of Washington, Seattle, WA. Contributed equally to this work.
authors.forename: Lisly
authors.initials: L
authors.lastname: Chéry
authors.affiliation: Department of Urology, University of Washington, Seattle, WA. Contributed equally to this work.
authors.forename: Hung-Ming
authors.initials: HM
authors.lastname: Lam
authors.affiliation: Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.affiliation: Department of Urology, University of Washington, Seattle, WA.
authors.forename: Bryce
authors.initials: B
authors.lastname: Lakely
authors.affiliation: Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Roger
authors.initials: R
authors.lastname: Coleman
authors.affiliation: Department of Urology, University of Washington, Seattle, WA.
authors.forename: Sandy
authors.initials: S
authors.lastname: Larson
authors.affiliation: Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Ichan School of Medicine at Mount Sinai, New York, NY.
authors.forename: Julio A
authors.initials: JA
authors.lastname: Aguirre-Ghiso
authors.affiliation: Divison of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Jing
authors.initials: J
authors.lastname: Xia
authors.affiliation: Divison of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Roman
authors.initials: R
authors.lastname: Gulati
authors.affiliation: Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA. Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Montgomery
authors.affiliation: Department of Veterans Affairs Medical Center, Seattle, WA. Department of Urology, University of Washington, Seattle, WA.
authors.forename: Paul
authors.initials: P
authors.lastname: Lange
authors.affiliation: Janssen Research and Development, LLC, Spring House, PA.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Snyder
authors.affiliation: Department of Veterans Affairs Medical Center, Seattle, WA. Department of Urology, University of Washington, Seattle, WA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.affiliation: Department of Urology, University of Washington, Seattle, WA.
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
mesh_terms: D018572:Disease-Free Survival; D015536:Down-Regulation; D015672:Erythroid Precursor Cells / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D059010:Single-Cell Analysis