Intrinsic transcriptional heterogeneity in neuroblastoma guides mechanistic and therapeutic insights

Abstract

Cell state is controlled by master transcription factors (mTFs) that determine the cellular gene expression program. Cancer cells acquire dysregulated gene expression programs by mutational and non-mutational processes. Intratumoral heterogeneity can result from cells displaying distinct mTF-regulated cell states, which co-exist within the tumor. One archetypal tumor associated with transcriptionally regulated heterogeneity is high-risk neuroblastoma (NB). Patients with NB have poor overall survival despite intensive therapies, and relapsed patients are commonly refractory to treatment. The cellular populations that comprise NB are marked by different cohorts of mTFs and differential sensitivity to conventional therapies. Recent studies have highlighted mechanisms by which NB cells dynamically shift the cell state with treatment, revealing new opportunities to control the cellular response to treatment by manipulating cell-state-defining transcriptional programs. Here, we review recent advances in understanding transcriptionally defined cancer heterogeneity. We offer challenges to the field to encourage translation of basic science into clinical benefit.

Keywords: cell state; core regulatory circuitry; epigenetics; heterogeneity; neuroblastoma.

Graphical abstract

Figure 1

Conceptual mechanisms by which changes in core regulatory circuitry members result in dysfunctional circuitries and oncogenesis (A) Regulatory circuitries are shown as genes (boxes) regulated by super-enhancer elements (SEs). These genes produce transcription factor protein products (ovals) that autoregulate their own loci and that of other TFs within the network. This produces a “balanced” core regulatory circuitry state. (B) This balanced state may be dysregulated by acquisition of a new oncogenic transcription factor member (TF4), which introduces protein-protein or protein-DNA interactions, interactions with RNA species, or co-activators, to co-opt the regulatory circuitry to an oncogenic outcome. (C) Loss of a transcription factor (TF3) that suppresses tumorigenesis, resulting in altered transcriptional activity, re-targeting of residual complexes to different gene loci, or both, resulting in oncogenesis. (D) Invasion of regulatory elements by oncogenic effectors (red box) such as MYC family TFs can induce mRNA amplification across single, collections of, or all genes, resulting in a dysregulated CRC.

Figure 2

Alterations in transcriptional circuitries results in acquisition of new phenotypes Regulatory circuitries are demonstrated genes (boxes) regulated by SEs. These genes produce transcription factor protein products (ovals) that autoregulate their own loci and that of other TFs within the network. Perturbation of this circuitry, by loss of TF3 and acquisition of TF4, results in a newly generated regulatory circuitry, with new genomic-binding loci. This causes alterations in the transcriptome, with a new cellular phenotype.

Figure 3

Principles of selection or interconversion of heterogeneous cancer-cell clones Two distinct models of adrenergic and mesenchymal clonal selection due to therapy in high-risk neuroblastoma are shown. (A) Tumors at diagnosis are heterogeneous populations. Adrenergic cells are depleted by conventional therapies, resulting in residual mesenchymal cells that repopulate the tumor, yielding a mesenchymal-dominant relapsed tumor. Here, adrenergic cells are found in the relapsed tumor due to subsequent stochastic interconversion of mesenchymal to adrenergic cells. (B) Tumor populations are globally reduced by therapy, affecting both adrenergic and mesenchymal cells. Residual cells undergo cell state switching, and treatment with conventional chemotherapies favor switching to a mesenchymal (MES) gene expression pattern. This results in re-population of tumors yielding mesenchymal-dominant relapsed tumors.