Trends in Cancer
OpinionSpecial Issue: Quantitative Cancer BiologyReconciling Non-Genetic Plasticity with Somatic Evolution in Cancer
Section snippets
Post-Treatment Tumor Progression
Many a new therapy fails to materialize its anticipated benefit despite a crisp mechanistic rationale for a therapeutic effect. In cancer treatment, the majority of new drugs, notably in ‘precision oncology’, fail to translate into meaningful patient benefit [1]. There are two broad classes of reasons for treatment failure in medicine. Often, the mediocre efficacy is due to insufficient intrinsic potency of the remedy in correcting the cause of disease, for instance: (i) an antimicrobial agent
The Default Explanation: Genetic Mutations in Somatic Evolution
The prevailing paradigm of Darwinian somatic evolution in cancer [3,15] for explaining tumor progression from initiation to aggressive, treatment-resistant cancer, posits that those tumor cells that happen to carry a random mutation, that in turn happens to confer a survival advantage, will be ‘selected for’. Iteration of (undirected) genetic diversification by mutations and selective clonal expansion drives progression. A variety of molecular mechanisms implement the selectable resistant
Cracks in the Paradigm of Cancer as a Genetic Disease
Accumulating findings that challenge the paradigm of genetic mutations and selection as the central mechanisms of tumor progression, comes from two types of studies: (i) at the genome level, including deep sequencing of tumor genomes; and (ii) at the phenotype level, notably using single-cell transcriptomics. The cell phenotype changes that appear after treatment are too diverse, too frequent, and too fast, to be accounted for by mutation/selection alone. Moreover, they are often reversible.
Non-Genetic Plasticity of Cell Phenotype
We can now turn to the second class of findings that soften the Darwinian paradigm of somatic evolution: non-genetic phenotype heterogeneity. The spontaneous production of distinct mammalian cell states within a cell type in an isogenic cell population and under uniform external conditions has been explicitly demonstrated using transcriptome analysis: cell population fractions that have been derived by physical cell sorting based on a particular trait from a clonal population exhibit
Distinct Enduring, Non-Genetic Cell States: Attractor States
That the dispersion of transcriptomic states in individual cells of the same type and clone, while driven by stochastic expression at each gene locus of the same genome, is not fully random [as the ‘dispersion of cells’ seen single-cell RNAseq results may suggest (Figure 2)], but has patterns, is of central importance and will now be explained.
Why does noise-driven transcriptome dispersion lead to cell states that endure (have a ‘memory’ of themselves) and represent distinct biological
Non-Genetic Dynamics in Tumors: Drug-Induced Stemness
We proposed above that cells incidentally driven by gene expression noise, that have entered an alternative attractor, could also be selected for if that attractor encodes an advantageous phenotype. This would satisfy the principle of random (spontaneous and undirected) production of a variant phenotype, that is required by the Darwinian scheme and is traditionally attributed to mutations [6]. But here is a difference: for cell phenotypes created non-genetically by attractor transition, gene
Reconciling Genetics with Non-Genetic Mechanism in Progression
After presenting the growing evidence for non-genetic plasticity in tumor cells and the theoretical principles that explain mutation-less acquisition of new functional phenotypes in response to treatment, we now ask how the traditional notion of mutation and selection fits into this burgeoning picture.
What happens to the GRN attractors when we randomly mutate a gene? Work in the past decades on artificial in silico GRNs, randomly wired but designed to mimic both architecture and dynamic
Concluding Remarks
We have discussed the mounting observations of non-genetic cell plasticity in cancer cells and its role in tumor progression, notably in post-therapy recurrence of more aggressive tumors that contain more stem-like cells. Such progression has traditionally been explained by Darwinian selection mutant cell clones. By contrast, ‘non-genetic explanations’ of tumor progression have long been sidelined, and hence, much of the accounts in this article are not new ideas. However, recent deep genome
Acknowledgments
The author thanks Ana Soto, Carlos Sonnenschein, Arja Kaipainen, Bernhard Strauss, Joseph Zhou, Ilya Shmulevich, Angela Pisco, Amy Brock, Michel Aguet, and Stuart Kauffman, and many other colleagues for stimulating discussions. This work was in part, supported by the National Institute of General Medical Sciences and the National Cancer Institute.
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