Cell state plasticity in neuroblastoma

Abstract

Evolving evidence indicates that tumor cells can transdifferentiate between distinct transcriptionally-determined cell states with changes in resultant phenotypes, a phenomenon known as cellular plasticity. These transitions are not driven by genetic mutations and typically in contrast to normal developmental processes, may proceed bidirectionally. Here, we review the role of cellular plasticity in the aggressive childhood solid tumor, neuroblastoma. We discuss the detection of two cell states, termed mesenchymal (MES) and adrenergic (ADRN), their properties and the transcriptional circuitries that control them, their relation to the normal embryogenesis of the sympathetic nervous system and their potential role in drug resistance, escape from therapy and development of relapse.

Keywords: Embryogenesis; Neuroblastoma; Plasticity.

Fig. 1.. Neuroblastoma cells display a range of cell states.

A. Initial studies demonstrated two distinct states (depicted by color), termed mesenchymal (MES) and adrenergic (ADRN), similar to N- and S-type cells. Switching from ADRN to MES states occurs in vitro and has been identified in the context of chemotherapies and genetic events, such as PRRX1 overexpression and loss of ARID1A. Whether this represents subclonal survival and expansion remains unknown. B. Subsequent studies identified the addition of new states, such as the retinoic acid-induced “retino-sympathetic” state, driven by distinct and overlapping master transcription factors from the ADRN state. C. It is hypothesized that neuroblastoma cells may exist in hybrid type cell states on a continuum between the polar extremes of ADRN and MES states. It is also likely that additional or distinct states exist, which may be induced or unmasked under the influence of genetic or therapeutic pressures, in addition to the influence of the tumor microenvironment. This enhances the range of states to consider, each of which may display unique malignant properties and therapeutic vulnerabilities, represented by a range of color, indicating the presence of heterogenous cell states in an individual tumor. Which of these state(s) is most relevant in the context of treatment approach, metastatic location/microenvironment and ultimately, tumor relapse, remains unknown. Figure created in Biorender.com.