Heterogeneity in brain tumors has been viewed through many lenses—from microscopes and experimental models to ‘omic’ analysis at the tissue and single-cell levels. Two studies now characterize patterns of DNA methylation and gene expression in single cells to reveal epigenomic underpinnings of cellular heterogeneity and plasticity in exquisite detail, including mechanistic insight into cellular transitions between stem-like and differentiated-like states.
Pathologists have long observed intratumoral heterogeneity in brain tumors, coining the name “glioblastoma multiforme” to reflect the diversity of their cellular forms. How different cellular forms arise from a shared genetic background and give rise to increasingly malignant and therapy-resistant states is under intense investigation. Only rare cells within human gliomas exhibit self-renewal and the ability to propagate tumors when implanted in the brains of mice. Such ‘glioma stem cells’ have been sought after as therapeutic targets to little avail. Powerful single-cell RNA sequencing approaches have revealed that in isocitrate dehydrogenase (IDH)-mutant gliomas, tumor cells recapitulate a hierarchical organization in which proliferative stem-like cells differentiate into glial-like progeny. By contrast, in IDH-wild-type gliomas, malignant cells exist on a continuum of stem-like and differentiated-like states between which they can reversibly shift. In this issue, two studies characterize the single-cell DNA methylomes of gliomas and also present expression and genetic analyses in the same cells or cell populations. These studies reveal epigenomic underpinnings of glioma heterogeneity and cellular plasticity, providing insight into mechanisms by which cells undergo state transitions and respond to environmental or therapeutic stress. Read more...
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