A Human Adult Stem Cell Signature Marks Aggressive Variants across Epithelial Cancers
Bryan A. Smith,
Nikolas G. Balanis,
Avinash Nanjundiah,
Katherine M. Sheu,
Brandon L. Tsai,
Qingfu Zhang,
Jung Wook Park,
Michael Thompson,
Jiaoti Huang,
Owen N. Witte,
Thomas G. Graeber
Affiliations
Bryan A. Smith
Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA 90095, USA
Nikolas G. Balanis
Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA
Avinash Nanjundiah
Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA
Katherine M. Sheu
Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA
Brandon L. Tsai
Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA 90095, USA
Qingfu Zhang
Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Pathology, The First Affiliated Hospital of China Medical University, 110001 Shenyang, China
Jung Wook Park
Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA 90095, USA
Michael Thompson
Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA
Jiaoti Huang
Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA
Owen N. Witte
Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA
Thomas G. Graeber
Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA; Corresponding author
Summary: Cancer progression to an aggressive phenotype often co-opts aspects of stem cell biology. Here, we developed gene signatures for normal human stem cell populations to understand the relationship between epithelial cancers and stem cell transcriptional programs. Using a pan-cancer approach, we reveal that aggressive epithelial cancers are enriched for a transcriptional signature shared by epithelial adult stem cells. The adult stem cell signature selected for epithelial cancers with worse overall survival and alterations of oncogenic drivers. Lethal small cell neuroendocrine lung, prostate, and bladder cancers transcriptionally converged onto the adult stem cell signature and not other stem cell signatures tested. We found that DNA methyltransferase expression correlated with adult stem cell signature status and was enriched in small cell neuroendocrine cancers. DNA methylation analysis uncovered a shared epigenomic profile between small cell neuroendocrine cancers. These pan-cancer findings establish a molecular link between human adult stem cells and aggressive epithelial cancers. : Smith et al. use a systems-level, human pan-stem cell approach to find that aggressive epithelial cancers, independent of tissue of origin, activate an adult stem cell expression program. They report that small cell neuroendocrine cancers from different tissues are molecularly linked to adult stem cells through a shared transcriptional and epigenomic profile. Keywords: stem cell signature, pan-cancer, neuroendocrine prostate cancer, small cell lung cancer, adult stem cells
