A Human Adult Stem Cell Signature Marks Aggressive Variants across Epithelial Cancers

Abstract

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.

N-Myc–mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer

“…Data from in vivo models revealed that N-Myc-driven prostate tumors are more aggressive following castration, including the development of metastatic lesions and the aberrant acquisition of alternative lineage programs. Whether or not these changes involve a transient, undifferentiated stem-like state (7,9,47) or a direct transdifferentiation (12) and the role of the local microenvironment in dictating the choice of lineage remains to be elucidated.…”

“…After long-term withdrawal, the response of AR target genes to androgen stimulation was dramatically reduced (over 80% for KLK4, Figure 3C). Moreover, expression of genes associated with the neural lineage was increased significantly in LNCaP-N-Myc cells ( Figure 3, C and D, and Supplemental Figure 4, C and D) and N-Myc expression led to increased enrichment on day 42 compared with day 4 for neural lineage and stem cell gene sets, including an adult stem cell signature associated with small-cell neuroendocrine cancers from multiple epithelial tissues (47). N-Myc expression was also associated with reduced global responsiveness to androgen restimulation, with fewer genes being differentially expressed on day 42 in LNCaP-N-Myc cells compared with LNCaP-CTL cells ( Figure 3E).…”

Pathway-guided analysis identifies Myc-dependent alternative pre-mRNA splicing in aggressive prostate cancers

“…SRSF3 itself has been recently shown to regulate splicing of NMD-determinant exons in chromatin modifier proteins during the induction of pluripotent stem cells (75). Given the role of Myc signaling in the acquisition of stem-like phenotypes and the stem-like state of advanced cancers, the mechanism that connects Myc overexpression to splicing changes in SRSF3 deserves further exploration (76,77).…”

The complexity of the serine glycine one-carbon pathway in cancer

“…Another important aspect of the SGOCP is its role in the control of stem cell function, which is of relevance because the expression of adult stem-like features is closely associated with cancers of a poor prognosis (Smith et al, 2018). The metabolic state of mouse embryonic stem cells (ESCs) has been linked to the use of threonine as a one-carbon donor through the upregulation of the enzyme threonine dehydrogenase (TDH; Wang et al, 2009).…”