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Genetic instability is invoked in explaining the cell phenotype changes that take place during cancer progression. However, the coexistence of a vast diversity of distinct clones, most prominently visible in the form of non-clonal chromosomal aberrations, suggests that Darwinian selection of mutant cells is not operating at maximal efficacy. Conversely, non-genetic instability of cancer cells must also be considered. Such mutation-independent instability of cell states is most prosaically manifest in the phenotypic heterogeneity within clonal cell populations or in the reversible switching between immature “cancer stem cell-like” and more differentiated states. How are genetic and non-genetic instability related to each other? Here, we review basic theoretical foundations and offer a dynamical systems perspective in which cancer is the inevitable pathological manifestation of modes of malfunction that are immanent to the complex gene regulatory network of the genome. We explain in an accessible, qualitative, and permissively simplified manner the mathematical basis for the “epigenetic landscape” and how the latter relates to the better known “fitness landscape.” We show that these two classical metaphors have a formal basis. By combining these two landscape concepts, we unite development and somatic evolution as the drivers of the relentless increase in malignancy. Herein, the cancer cells are pushed toward cancer attractors in the evolutionarily unused regions of the epigenetic landscape that encode more and more “dedifferentiated” states as a consequence of both genetic (mutagenic) and non-genetic (regulatory) perturbations—including therapy. This would explain why for the cancer cell, the principle of “What does not kill me makes me stronger” is as much a driving force in tumor progression and development of drug resistance as the simple principle of “survival of the fittest.”

The notion of epigenetic \"marks\" used by molecular biologists is conceptually disconnected from the idea of Waddington's epigenetic \"landscape\" that is used by systems biologists and biophysicists. Recent advances suggest that these 2 distinct schools of thought could be united.

Cell migration in the \"correct\" direction is pivotal for many biological processes. Although most work is devoted to its molecular mechanisms, the cell's preference for one direction over others, thus overcoming intrinsic random motility, epitomizes a profound principle that underlies all complex systems: the choice of one axis, in structure or motion, from a uniform or symmetric set of options. Explaining directional motility by an external chemo-attractant gradient does not solve but only shifts the problem of causation: whence the gradient? A new study in PLOS Biology shows cell migration in a self-generated gradient, offering an opportunity to take a broader look at the old dualism of extrinsic instruction versus intrinsic symmetry-breaking in cell biology.

Polarization of cell phenotypes, a common strategy to achieve cell type diversity in metazoa, results from binary cell-fate decisions in the branching pedigree of development. Such \"either-or\" fate decisions are controlled by two opposing cell fate-determining transcription factors. Each of the two distinct \"master regulators\" promotes differentiation of its respective sister lineage. But they also suppress one other, leading to their mutually exclusive expression in the two ensuing lineages. Thus, promiscuous coexistence of the antagonist regulators in the same cell, the hallmark of the common \"undecided\" progenitor of two sister lineages, is considered unstable. This antagonism ensures robust polarization into two discretely distinct cell types. But now the immune system's T-helper (Th) cells and their two canonical subtypes, Th1 and Th2 cells, tell a different story, as revealed in three papers recently published in PLOS Biology. The intermediate state that co-expresses the two opposing master regulators of the Th1 and Th2 subtypes, T-bet and Gata3, is highly stable and is not necessarily an undecided precursor. Instead, the Th1/Th2 hybrid cell is a robust new type with properties of both Th1 and Th2 cells. These hybrid cells are functionally active and possess the benefit of moderation: self-limitation of effector T cell function to prevent excessive inflammation, a permanent risk in host defense that can cause tissue damage or autoimmunity. Gene regulatory network analysis suggests that stabilization of the intermediate center in a polarizing system can be achieved by minor tweaking of the architecture of the mutual suppression gene circuit, and thus is a design option readily available to evolution.

  [...]the accumulating evidence of transcriptionally induced transdifferentiation between lineages--pioneered by Weintraub [8] and Graf [9] and culminating in the recently achieved, easily reproduced reprogramming of adult cells into \"induced pluripotent stem\" (iPS) cells by overexpression of pluripotency transcription factors [10]--has refuted the dogma of cell fate irreversibility Choosing between Primitive Endoderm and Epiblast: Not Black and White The article by Brickman and coworkers (Canham et al., this issue of PLoS Biology [11]) is the latest in a recent series of reports (reviewed in [12] and [13]; [14]-[18]) that have begun to challenge the view that embryonic cells undergo a tightly controlled, predestined one-way journey from totipotency to pluripotency towards specific lineages. [...]specific network dynamics may be dedicated to either promoting exploration of marginal regions [20] or to limiting its dispersion, akin to \"noise suppression,\" which would stabilize the ground state and hence maintain pluripotency [38]. [...]the artificial conditions in cell culture that define ES cells may fail to recapitulate the physiological cascade of events in the embryo environment that would naturally disperse and destabilize the cloud of pluripotent states, forcing cells to follow entropy and, in their journey that is constrained by the gene regulatory network interactions, populate the various peripheral regions of the state space.

Genome sequencing of cancer and normal tissues, alongside single-cell transcriptomics, continues to produce findings that challenge the idea that cancer is a ‘genetic disease’, as posited by the somatic mutation theory (SMT). In this prevailing paradigm, tumorigenesis is caused by cancer-driving somatic mutations and clonal expansion. However, results from tumor sequencing, motivated by the genetic paradigm itself, create apparent ‘paradoxes’ that are not conducive to a pure SMT. But beyond genetic causation, the new results lend credence to old ideas from organismal biology. To resolve inconsistencies between the genetic paradigm of cancer and biological reality, we must complement deep sequencing with deep thinking: embrace formal theory and historicity of biological entities, and (re)consider non-genetic plasticity of cells and tissues. In this Essay, we discuss the concepts of cell state dynamics and tissue fields that emerge from the collective action of genes and of cells in their morphogenetic context, respectively, and how they help explain inconsistencies in the data in the context of SMT.

Tryptophan, an essential dietary amino acid, is metabolized into various metabolites within both gut microbiota and tissue cells. These metabolites have demonstrated potential associations with panvascular diseases. However, the specific relationship between tryptophan metabolism, particularly Indole-3-aldehyde (3-IAId), and the occurrence of aortic dissection (AD) remains unclear. 3-IAId showed an inverse association with advanced atherosclerosis, a risk factor for AD. In this study, we employed a well-established β-aminopropionitrile monofumarate (BAPN)-induced AD murine model to investigate the impact of 3-IAId treatment on the progression of AD. Our results reveal compelling evidence that the administration of 3-IAId significantly mitigated aortic dissection and rupture rates (BAPN + 3-IAId vs. BAPN, 45% vs. 90%) and led to a notable reduction in mortality rates (BAPN + 3-IAId vs. BAPN, 20% vs. 55%). Furthermore, our study elucidates that 3-IAId exerts its beneficial effects by inhibiting the phenotype transition of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic state. It also mitigates extracellular matrix degradation, attenuates macrophage infiltration, and suppresses the expression of inflammatory cytokines, collectively contributing to the attenuation of AD development. Our findings underscore the potential of 3-IAId as a promising intervention strategy for the prevention of thoracic aortic dissection, thus providing valuable insights into the realm of vascular disease management.

Pluripotency: Cell-to-cell variations Even in clonal populations of cells, there is significant phenotypic variation from cell to cell. This could reflect the 'noise' inherent in gene expression: or the various cell states could represent stable phenotypic variants. Chang et al . analysed the behaviour of an 'outlier' in clonal populations of mouse haematoipoietic stem cells that had very high expressions of the stem cell marker Sca-1 and found that outliers possessed distinct transcriptomes. Though the transcriptomes eventually reverted back to that of the median cells, while they differed they could drive the cells to express characteristics of distinct cell fates. Thus clonal heterogeneity of gene expression may not be due to noise in the expression of individual genes, but rather is a manifestation of metastable states of a slowly fluctuating transcriptome. These fluctuations may govern the reversible, stochastic priming of multipotent progenitor cells in cell fate decision. Even in clonal populations of cells, there is significant phenotypic variation from cell to cell: Huang and colleagues analyse the behaviour of an 'outlier', which had very high expressions of the stem cell marker Sca-1, and conclude that clonal heterogeneity of gene expression level is a manifestation of metastable states of a slowly fluctuating transcriptome. These fluctuations may govern the reversible, stochastic priming of multipotent progenitor cells in cell fate decision. (See Nature Reports Stem Cells). Phenotypic cell-to-cell variability within clonal populations may be a manifestation of ‘gene expression noise’ 1 , 2 , 3 , 4 , 5 , 6 , or it may reflect stable phenotypic variants 7 . Such ‘non-genetic cell individuality’ 7 can arise from the slow fluctuations of protein levels 8 in mammalian cells. These fluctuations produce persistent cell individuality, thereby rendering a clonal population heterogeneous. However, it remains unknown whether this heterogeneity may account for the stochasticity of cell fate decisions in stem cells. Here we show that in clonal populations of mouse haematopoietic progenitor cells, spontaneous ‘outlier’ cells with either extremely high or low expression levels of the stem cell marker Sca-1 (also known as Ly6a; ref. 9 ) reconstitute the parental distribution of Sca-1 but do so only after more than one week. This slow relaxation is described by a gaussian mixture model that incorporates noise-driven transitions between discrete subpopulations, suggesting hidden multi-stability within one cell type. Despite clonality, the Sca-1 outliers had distinct transcriptomes. Although their unique gene expression profiles eventually reverted to that of the median cells, revealing an attractor state, they lasted long enough to confer a greatly different proclivity for choosing either the erythroid or the myeloid lineage. Preference in lineage choice was associated with increased expression of lineage-specific transcription factors, such as a >200-fold increase in Gata1 (ref. 10 ) among the erythroid-prone cells, or a >15-fold increased PU.1 (Sfpi1) (ref. 11 ) expression among myeloid-prone cells. Thus, clonal heterogeneity of gene expression level is not due to independent noise in the expression of individual genes, but reflects metastable states of a slowly fluctuating transcriptome that is distinct in individual cells and may govern the reversible, stochastic priming of multipotent progenitor cells in cell fate decision.

Intratumor cellular heterogeneity and non-genetic cell plasticity in tumors pose a recently recognized challenge to cancer treatment. Because of the dispersion of initial cell states within a clonal tumor cell population, a perturbation imparted by a cytocidal drug only kills a fraction of cells. Due to dynamic instability of cellular states the cells not killed are pushed by the treatment into a variety of functional states, including a “stem-like state” that confers resistance to treatment and regenerative capacity. This immanent stress-induced stemness competes against cell death in response to the same perturbation and may explain the near-inevitable recurrence after any treatment. This double-edged-sword mechanism of treatment complements the selection of preexisting resistant cells in explaining post-treatment progression. Unlike selection, the induction of a resistant state has not been systematically analyzed as an immanent cause of relapse. Here, we present a generic elementary model and analytical examination of this intrinsic limitation to therapy. We show how the relative proclivity towards cell death versus transition into a stem-like state, as a function of drug dose, establishes either a window of opportunity for containing tumors or the inevitability of progression following therapy. The model considers measurable cell behaviors independent of specific molecular pathways and provides a new theoretical framework for optimizing therapy dosing and scheduling as cancer treatment paradigms move from “maximal tolerated dose,” which may promote therapy induced-stemness, to repeated “minimally effective doses” (as in adaptive therapies), which contain the tumor and avoid therapy-induced progression.

The development of drug resistance, the prime cause of failure in cancer therapy, is commonly explained by the selection of resistant mutant cancer cells. However, dynamic non-genetic heterogeneity of clonal cell populations continuously produces metastable phenotypic variants (persisters), some of which represent stem-like states that confer resistance. Even without genetic mutations, Darwinian selection can expand these resistant variants, which would explain the invariably rapid emergence of stem-like resistant cells. Here, by using quantitative measurements and modelling, we show that appearance of multidrug resistance in HL60 leukemic cells following treatment with vincristine is not explained by Darwinian selection but by Lamarckian induction. Single-cell longitudinal monitoring confirms the induction of multidrug resistance in individual cells. Associated transcriptome changes indicate a lasting stress response consistent with a drug-induced switch between high-dimensional cancer attractors. Resistance induction correlates with Wnt pathway upregulation and is suppressed by β-catenin knockdown, revealing a new opportunity for early therapeutic intervention against the development of drug resistance. Many different factors contribute to the acquisition of drug resistance in cancer cells. Using single-cell analyses of leukaemia cells, the authors here provide evidence for an inductive mode of resistance, where cells express MDR1 in response to drug exposure, rather than selection of pre-existing, partially resistant cells.