Distance in cancer gene expression from stem cells predicts patient survival

Abstract

The degree of histologic cellular differentiation of a cancer has been associated with prognosis but is subjectively assessed. We hypothesized that information about tumor differentiation of individual cancers could be derived objectively from cancer gene expression data, and would allow creation of a cancer phylogenetic framework that would correlate with clinical, histologic and molecular characteristics of the cancers, as well as predict prognosis. Here we utilized mRNA expression data from 4,413 patient samples with 7 diverse cancer histologies to explore the utility of ordering samples by their distance in gene expression from that of stem cells. A differentiation baseline was obtained by including expression data of human embryonic stem cells (hESC) and human mesenchymal stem cells (hMSC) for solid tumors, and of hESC and CD34+ cells for liquid tumors. We found that the correlation distance (the degree of similarity) between the gene expression profile of a tumor sample and that of stem cells orients cancers in a clinically coherent fashion. For all histologies analyzed (including carcinomas, sarcomas, and hematologic malignancies), patients with cancers with gene expression patterns most similar to that of stem cells had poorer overall survival. We also found that the genes in all undifferentiated cancers of diverse histologies that were most differentially expressed were associated with up-regulation of specific oncogenes and down-regulation of specific tumor suppressor genes. Thus, a stem cell-oriented phylogeny of cancers allows for the derivation of a novel cancer gene expression signature found in all undifferentiated forms of diverse cancer histologies, that is competitive in predicting overall survival in cancer patients compared to previously published prediction models, and is coherent in that gene expression was associated with up-regulation of specific oncogenes and down-regulation of specific tumor suppressor genes associated with regulation of the multicellular state.

Cancer stem cells as key drivers of tumour progression

“…Riester et al analysed mRNA expression data of histologically diverse cancer samples in comparison to gene expression in stem cell samples including human embryonic stem cells, human mesenchymal stem cells and CD34+ hematopoietic stem cells. The authors found that poor overall survival is correlated with gene expression signatures with the most similar expression to that of stem cells [ 160 ]. While it remains to be determined the extent of the overlap between these tissues specific metastatic program to the expression profile of CSCs, evidence have shown that metastatic cancer possess distinct stem-like gene expression signatures [ 161 – 163 ].…”

A ‘Goldmine’ for digging cancer-specific targets: the genes essential for embryo development but non-essential for adult life

“…Cancers, particularly those poorly differentiated cancers including the high-grade ER-negative breast cancers, glioblastomas, and bladder carcinomas, also express ES cell gene signatures ( Ben-Porath et al., 2008 ). Patients with cancers expressing a gene signature similar to that of stem cells exhibit poor overall survival ( Riester et al., 2017 ). Similarities between embryonic cells and cancer cells are also found in DNA methylation patterns and pioneer transcription factors and architectural proteins that regulate chromatin organization ( Larson and Yuan, 2012 ; Chiang et al., 2014 ; Dobersch et al., 2019 ).…”

Evidence of Antitumor and Antimetastatic Potential of Induced Pluripotent Stem Cell-Based Vaccines in Cancer Immunotherapy

“…One important discovery reported here is related to the possibility of generating anti-cancer immunity not just toward "bulk" cancer cells but also toward primitive de-differentiated CSC-like MammoSphere cells. Indeed, in several cancers, gene expression programs have been identified to be similar to those of embryonic pluripotent stem cells, namely, a "stemness" profile which is associated to oncogenic de-differentiation in epithelial cancer progression by a gradual loss of a differentiated phenotype and acquisition of progenitor and stem cell-like features (7,8,57).…”