Non-genetic cancer cell plasticity and therapy-induced stemness in tumour relapse: 'What does not kill me strengthens me'

Abstract

Therapy resistance and tumour relapse after drug therapy are commonly explained by Darwinian selection of pre-existing drug-resistant, often stem-like cancer cells resulting from random mutations. However, the ubiquitous non-genetic heterogeneity and plasticity of tumour cell phenotype raises the question: are mutations really necessary and sufficient to promote cell phenotype changes during tumour progression? Cancer therapy inevitably spares some cancer cells, even in the absence of resistant mutants. Accumulating observations suggest that the non-killed, residual tumour cells actively acquire a new phenotype simply by exploiting their developmental potential. These surviving cells are stressed by the cytotoxic treatment, and owing to phenotype plasticity, exhibit a variety of responses. Some are pushed into nearby, latent attractor states of the gene regulatory network which resemble evolutionary ancient or early developmental gene expression programs that confer stemness and resilience. By entering such stem-like, stress-response states, the surviving cells strengthen their capacity to cope with future noxious agents. Considering non-genetic cell state dynamics and the relative ease with which surviving but stressed cells can be tipped into latent attractors provides a foundation for exploring new therapeutic approaches that seek not only to kill cancer cells but also to avoid promoting resistance and relapse that are inherently linked to the attempts to kill them.

Figure 1

State transition and non-genetic plasticity. The cellular transition from the state with X^High (red) to X^Low (blue) and vice versa can be thought of as a state transition between the two subattractors on the epigenetic landscape (see Box 1). The reversibility of such switching and the clonality of the populations in which both states coexist indicate that such cell phenotype changes are not caused by mutations. As in multistable systems, the transition is noise driven but modulated by external conditions, including the presence of the drug. Note that by monitoring one dimension of the gene expression state space, for example, X=MDR1 expression, we are able to observe cell transition only as a projection (horizontal axis) and do not know what happens in orthogonal (non-observable) dimensions.

Figure 2

Two schemes for the evolution of drug-resistant state. (A) In the first scenario, according to the Darwinian selection, the drug-resistant phenotype results from selection of resistant clones, which were produced by genetic mutations. The genetic mutation alters the genome, causing a rewiring of the gene regulatory network (GRN), which in turn changes the epigenetic landscape, creating a new phenotype (attractor state, S(X^High)). (B) In the second scenario, the drug causes an attractor transition from the sensitive (blue) to the resistant (red) state in a multistable system (landscape with two potential wells). The GRN and the landscape remain unchanged.

Figure 3

Different anticancer therapy schemes can minimise the strengthening of surviving cells. If rather than treating the tumour using conventional, aggressive therapy that may stimulate the stressed, stem-like (=more aggressive) state, cancer is treated using alternative, gentler modification of cell growth we might be able to control the ratio between the stressed cells and the naive, non-stressed cancer cells. The idea of treating cancer as a chronic disease is to prevent the cells from transiting into the aggressive state in response to cytotoxic stress. This can be achieved by blocking transition into that state (right blue arrow) or by containing cells without cytotoxity, for example, by promoting differentiation (green arrow).