The epipliancy journey: Tumor initiation at the mercy of identity crisis and epigenetic drift.

Cellular pliancy refers to the unique disposition of different stages of cellular differentiation to transform when exposed to specific oncogenic insults. This concept highlights a strong interconnection between cellular identity and tumorigenesis, and implies overcoming of epigenetic barriers defining cellular states. Emerging evidence suggests that the cell-type-specific response to intrinsic and extrinsic stresses is modulated by accessibility to certain areas of the genome. Understanding the interplay between epigenetic mechanisms, cellular differentiation, and oncogenic insults is crucial for deciphering the complex nature of tumorigenesis and developing targeted therapies. Hence, cellular pliancy relies on a dynamic cooperation between the cellular identity and the cellular context through epigenetic control, including the reactivation of cellular mechanisms, such as epithelial-to-mesenchymal transition (EMT). Such mechanisms and pathways confer plasticity to the cell allowing it to adapt to a hostile environment in a context of tumor initiation, thus changing its cellular identity. Indeed, growing evidence suggests that cancer is a disease of cell identity crisis, whereby differentiated cells lose their defined identity and gain progenitor characteristics. The loss of cell fate commitment is a central feature of tumorigenesis and appears to be a prerequisite for neoplastic transformation. In this context, EMT-inducing transcription factors (EMT-TFs) cooperate with mitogenic oncoproteins to foster malignant transformation. The aberrant activation of EMT-TFs plays an active role in tumor initiation by alleviating key oncosuppressive mechanisms and by endowing cancer cells with stem cell-like properties, including the ability to self-renew, thus changing the course of tumorigenesis. This highly dynamic phenotypic change occurs concomitantly to major epigenome reorganization, a key component of cell differentiation and cancer cell plasticity regulation. The concept of pliancy was initially proposed to address a fundamental question in cancer biology: why are some cells more likely to become cancerous in response to specific oncogenic events at particular developmental stages? We propose the concept of epipliancy, whereby a difference in epigenetic configuration leads to malignant transformation following an oncogenic insult. Here, we present recent studies furthering our understanding of how the epigenetic landscape may impact the modulation of cellular pliancy during early stages of cancer initiation.