Evidence from numerous cancers suggests that increased aggressiveness is accompanied by up-regulation of signaling pathways and acquisition of properties common to stem cells. It is unclear if different subtypes of late-stage cancer vary in stemness properties and whether or not these subtypes are transcriptionally similar to normal tissue stem cells.
We report a gene signature specific for human prostate basal cells that is differentially enriched in various phenotypes of late-stage metastatic prostate cancer. We FACS-purified and transcriptionally profiled basal and luminal epithelial populations from the benign and cancerous regions of primary human prostates. High-throughput RNA sequencing showed the basal population to be defined by genes associated with stem cell signaling programs and invasiveness. Application of a 91-gene basal signature to gene expression datasets from patients with organ-confined or hormone-refractory metastatic prostate cancer revealed that metastatic small cell neuroendocrine carcinoma was molecularly more stem-like than either metastatic adenocarcinoma or organ-confined adenocarcinoma. Bioinformatic analysis of the basal cell and two human small cell gene signatures identified a set of E2F target genes common between prostate small cell neuroendocrine carcinoma and primary prostate basal cells. Taken together, our data suggest that aggressive prostate cancer shares a conserved transcriptional program with normal adult prostate basal stem cells.
Proceedings of the National Academy of Sciences of the United States of America. 2015 Oct 12 [Epub ahead of print]
Bryan A Smith, Artem Sokolov, Vladislav Uzunangelov, Robert Baertsch, Yulia Newton, Kiley Graim, Colleen Mathis, Donghui Cheng, Joshua M Stuart, Owen N Witte
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095;, Center for Biomolecular Science and Engineering, University of California, Santa Cruz, CA 95064;, Department of Biomolecular Engineering, University of California, Santa Cruz, CA 95064;, Center for Biomolecular Science and Engineering, University of California, Santa Cruz, CA 95064;, Department of Biomolecular Engineering, University of California, Santa Cruz, CA 95064;, Department of Biomolecular Engineering, University of California, Santa Cruz, CA 95064;, Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095;, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095;, Center for Biomolecular Science and Engineering, University of California, Santa Cruz, CA 95064; Department of Biomolecular Engineering, University of California, Santa Cruz, CA 95064; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095