Transcriptome analysis reveals high tumor heterogeneity with respect to re-activation of stemness and proliferation programs

PLoS One. 2022 May 19;17(5):e0268626. doi: 10.1371/journal.pone.0268626. eCollection 2022.

Abstract

Significant alterations in signaling pathways and transcriptional regulatory programs together represent major hallmarks of many cancers. These, among all, include the reactivation of stemness, which is registered by the expression of pathways that are active in the embryonic stem cells (ESCs). Here, we assembled gene sets that reflect the stemness and proliferation signatures and used them to analyze a large panel of RNA-seq data from The Cancer Genome Atlas (TCGA) Consortium in order to specifically assess the expression of stemness-related and proliferation-related genes across a collection of different tumor types. We introduced a metric that captures the collective similarity of the expression profile of a tumor to that of ESCs, which showed that stemness and proliferation signatures vary greatly between different tumor types. We also observed a high degree of intertumoral heterogeneity in the expression of stemness- and proliferation-related genes, which was associated with increased hazard ratios in a fraction of tumors and mirrored by high intratumoral heterogeneity and a remarkable stemness capacity in metastatic lesions across cancer cells in single cell RNA-seq datasets. Taken together, these results indicate that the expression of stemness signatures is highly heterogeneous and cannot be used as a universal determinant of cancer. This calls into question the universal validity of diagnostic tests that are based on stem cell markers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation / genetics
  • Embryonic Stem Cells
  • Gene Expression Profiling*
  • Humans
  • Neoplasms* / pathology
  • Neoplastic Stem Cells / pathology
  • Transcriptome
  • Whole Exome Sequencing

Grant support

DPe acknowledges the Russian Science Foundation grant 21-64-00006. TI acknowledges the Russian Foundation for Basic Research grant 19-34-90174. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.