Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways
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Lisly Chéry1,*, Hung-Ming Lam1,*, Ilsa Coleman2, Bryce Lakely1, Roger Coleman2, Sandy Larson1, Julio A. Aguirre-Ghiso3, Jing Xia4, Roman Gulati4, Peter S. Nelson2,5, Bruce Montgomery5, Paul Lange6,1, Linda A. Snyder7, Robert L. Vessella6,1 and Colm Morrissey1
1 Department of Urology, University of Washington, Seattle, WA
2 Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA
3 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
4 Divison of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
5 Department of Medicine, University of Washington, Seattle, WA
6 Department of Veterans Affairs Medical Center, Seattle, WA
7 Janssen Research and Development, LLC, Spring House, PA
* These authors contributed equally to this work
Colm Morrissey , email:
Keywords: Prostate cancer, dormancy, metastasis, p38, gene expression
Received: July 03, 2014 Accepted: September 15, 2014 Published: September 16, 2014
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.
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