Envisioning metastasis as a transdifferentiation phenomenon clarifies discordant results on cancer

Abstract

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.

Epigenetic activation of the small GTPase TCL contributes to colorectal cancer cell migration and invasion

“…For instance, an interaction between MRTF-A and the histone H3K4 methyltransferase complex COMPASS results in activation of MMP9 transcription and augmented migration/invasion of lung cancer cells 37 . Jehanno et al have observed that a dynamic association between MRTF-A activity and H3K9 methylation status may account for breast cancer metastasis 41 . In addition, recruitment of histone acetyltransferase CBP/ p300 by MRTF-A has been found to be a rate-limiting step in metastasis-related transcriptional events in cancer cells 38,42,43 .…”

A model of dynamic stability of H3K9me3 heterochromatin to explain the resistance to reprogramming of differentiated cells

“…Certain reports on H3K9me3 in cancer are however conflicting since an increase of H3K9me3 and SUV39H1 activity has also been observed in malignant cells. This seeming paradox could in fact have been expected if considering the contractile phenotype of metastatic cells as a secondary differentiation state different from that of the cell at the origin of the cancer, for instance epithelial [23].…”