Envisioning metastasis as a transdifferentiation phenomenon clarifies discordant results on cancer.

Cancer is generally conceived as a dedifferentiation process in which quiescent post-mitotic differentiated cells acquire stem-like properties and the capacity to proliferate. This view holds for the initial stages of carcinogenesis but is more questionable for advanced stages when the cells can transdifferentiate into the contractile phenotype associated to migration and metastasis. Singularly from this perspective, the hallmark of the most aggressive cancers would correspond to a genuine differentiation status, even if it is different from the original one. This seeming paradox could help reconciling discrepancies in the literature about the pro- or anti-tumoral functions of candidate molecules involved in cancer and whose actual effects depend on the tumoral grade. These ambiguities which are likely to concern a myriad of molecules and pathways, are illustrated here with the selected examples of chromatin epigenetics and myocardin-related transcription factors, using the human MCF10A and MCF7 breast cancer cells. Self-renewing stem like cells are characterized by a loose chromatin with low levels of the H3K9 trimetylation, but high levels of this mark can also appear in cancer cells acquiring a contractile-type differentiation state associated to metastasis. Similarly, the myocardin-related transcription factor MRTF-A is involved in metastasis and epithelial-mesenchymal transition, whereas this factor is naturally enriched in the quiescent cells which are precisely the most resistant to cancer: cardiomyocytes. These seeming paradoxes reflect the bistable epigenetic landscape of cancer in which dedifferentiated self-renewing and differentiated migrating states are incompatible at the single cell level, though coexisting at the population level.

Drawing a Waddington landscape to capture dynamic epigenetics.

Epigenetics is most often reduced to chromatin marking in the current literature, whereas this notion was initially defined in a more general context. This restricted view ignores that epigenetic memories are in fact more robustly ensured in living systems by steady-state mechanisms with permanent molecule renewal. This misconception is likely to result from misleading intuitions and insufficient dialogues between traditional and quantitative biologists. To demystify dynamic epigenetics, its most famous image, a Waddington landscape and its attractors, are explicitly drawn. The simple example provided, is sufficient to highlight the main requirements and characteristics of dynamic gene networks, underlying cellular differentiation, de-differentiation and trans-differentiation.

Epigenetic memories: structural marks or active circuits?

A hallmark of living systems is the management and the storage of information through genetic and epigenetic mechanisms. Although the notion of epigenetics was originally given to any regulation beyond DNA sequence, it has often been restricted to chromatin modifications, supposed to behave as cis-markers, specifying the sets of genes to be expressed or repressed. This definition does not take into account the initial view of epigenetics, based on nonlinear interaction networks whose "attractors" can remain stable without need for any chromatin mark. In addition, most chromatin modifications are the steady state resultants of highly dynamic modification and de-modification activities and, as such, seem poorly appropriate to work as long-term memory keepers. Instead, the basic support of epigenetic memory could remain the attractors, to which chromatin modifications belong as do many other components. The influence of chromatin modifications in memory is highly questionable when envisioned as static structural marks, but can be recovered under the dynamic circuitry perspective, thanks to their self-templating properties. Beside their standard repressive or permissive functions, chromatin modifications can also influence transcription in multiple ways such as: (1) by randomizing or inversely stabilizing gene expression, (2) by mediating cooperativity between pioneer and secondary transcription factors, and (3) in the hysteresis and the ultrasensitivity of gene expression switches, allowing the cells to take unambiguous transcriptional decisions.

A dynamic model of transcriptional imprinting derived from the vitellogenesis memory effect.

Transcriptional memory of transient signals can be imprinted on living systems and influence their reactivity to repeated stimulations. Although they are classically ascribed to structural chromatin rearrangements in eukaryotes, such behaviors can also rely on dynamic memory circuits with sustained self-amplification loops. However, these phenomena are either of finite duration, or conversely associated to sustained phenotypic changes. A mechanism is proposed, in which only the responsiveness of the target gene is durably reset at a higher level after primary stimulation, using the celebrated but still puzzling vitellogenesis memory effect. The basic ingredients of this system are: 1), a positive autoregulation of the estrogen receptor α gene; 2), a strongly cooperative action of the estradiol receptor on vitellogenin expression; and 3), a variant isoform of the estradiol receptor with two autonomous transcription-activating modules, one of which is signal-independent and the other, signal-dependent. Realistic quantification supports the possibility of a multistationary situation in which ligand-independent activity is unable by itself to prime the amplification loop, but can click the system over a memory threshold after a primary stimulation. This ratchet transcriptional mechanism can have developmental and ecotoxicological importance and explain lifelong imprinting of past exposures without apparent phenotypic changes before restimulation and without need for persistent chromatin modifications.