Cancer cell states and emergent properties of the dynamic tumor system

Abstract

Phenotypic heterogeneity within malignant cells of a tumor is emerging as a key property of tumorigenesis. Recent work using single-cell transcriptomics has led to the identification of distinct cancer cell states across a range of cancer types, but their functional relevance and the advantage that they provide to the tumor as a system remain elusive. We present here a definition of cancer cell states in terms of coherently and differentially expressed gene modules and review the origins, dynamics, and impact of states on the tumor system as a whole. The spectrum of cell states taken on by a malignant population may depend on cellular lineage, epigenetic history, genetic mutations, or environmental cues, which has implications for the relative stability or plasticity of individual states. Finally, evidence has emerged that malignant cells in different states may cooperate or compete within a tumor niche, thereby providing an evolutionary advantage to the tumor through increased immune evasion, drug resistance, or invasiveness. Uncovering the mechanisms that govern the origin and dynamics of cancer cell states in tumorigenesis may shed light on how heterogeneity contributes to tumor fitness and highlight vulnerabilities that can be exploited for therapy.

Figure 1.

A gene module framework to characterize cancer cell states. (A) Gene modules emerge from the underlying gene regulatory network. Nodes and edges represent genes and coexpression, respectively. Colors indicate distinct gene modules. (B) Coherent gene modules interact with other modules to define a malignant cell's state. (C) The spectrum of states available to a cell can be described as a state potential map, where some states are shared across patients, cancer types, cell types, or clones for example, whereas others are accessible only in particular contexts.

Figure 2.

Cell- and system-level view of intratumor heterogeneity. (Top) Intrinsic factors (genetic alterations or epigenetic changes) and extrinsic factors (stimuli from the environment) lead to transcriptional changes, represented here with the expression of two genes (orange and purple). (Bottom) Transcriptional heterogeneity is revealed by scRNA-seq, which gives the gene expression profile of each cell. Histograms depict expression profiles corresponding to different cancer cell states in which two genes (orange and purple lines) are expressed at different levels. Within the tumor, cancer cells may also compete or cooperate with each other and interact with other cells of the tumor microenvironment. Intrinsic epigenetic factors may induce the EMT. Low vascularization and oxygen levels (O₂) may induce the hypoxic state, which in turn promotes angiogenesis through VEGFA secretion. Interferon gamma (IFNG) secretion by T cells may lead to an interferon response state with high CD274 (also known as PDL1) expression.