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Cellular plasticity and transitional phenotypes add to complexities of cancer metastasis that can be initiated by single cell epithelial to mesenchymal transition (EMT) or cooperative cell migration (CCM). Our study identifies novel regulatory cross-talks between Tcf21 and Slug in mediating phenotypic and migration plasticity in high-grade serous ovarian adenocarcinoma (HGSC). Differential expression and subcellular localization associate Tcf21, Slug with epithelial, mesenchymal phenotypes, respectively; however, gene manipulation approaches identify their association with additional intermediate phenotypic states, implying the existence of a multistep epithelial-mesenchymal transition program. Live imaging further associated distinct migratory modalities with the Tcf21/Slug status of cell systems and discerned proliferative/passive CCM, active CCM and EMT modes of migration. Tcf21-Slug balance identified across a phenotypic spectrum in HGSC cell lines, associated with microenvironment-induced transitions and the emergence of an epithelial phenotype following drug exposure. Phenotypic transitions and associated functionalities following drug exposure were affirmed to ensue from occupancy of Slug promoter E-box sequences by Tcf21. Our study effectively provides a framework for understanding the relevance of ovarian cancer plasticity as a function of two transcription factors., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The concept of cancer as a stem cell disease has slowly gained ground over the last decade. A 'stem-like' state essentially necessitates that some cells in the developing tumor express the properties of remaining quiescent, self-renewing and regenerating tumors through establishment of aberrant cellular hierarchies. Alternatively, such capacities may also be reacquired through a de-differentiation process. The abnormal cellular differentiation patterns involved during either process during carcinogenesis are likely to be driven through a combination of genetic events and epigenetic regulation. The role(s) of the latter is increasingly being appreciated in acquiring the requisite genomic specificity and flexibility required for phenotypic plasticity, specifically in a context wherein genome sequences are not altered for differentiation to ensue. In this chapter, the recent advances in elucidating epigenetic mechanisms that govern the self-renewal, differentiation and regenerative potentials of cancer stem cells will be presented.

"Epigenetic plasticity" refers to the capability of mammalian cells to alter their differentiation status via chromatin remodeling-associated alterations in gene expression. While epigenetic plasticity has been best associated with lineage commitment of embryonic stem cells, recent studies have demonstrated chromatin remodeling even in terminally differentiated normal cells, and advanced-stage melanoma and breast cancer cells, in context-dependent responses to alterations in their microenvironment. In the current study, we extend this attribute of epigenetic plasticity to aggressive ovarian cancer cells, by using an integrative approach to associate cellular phenotypes with chromatin modifications ("ChIP-chip") and mRNA and microRNA expression. While we identified numerous gene promoters possessing the well-known "bivalent mark" of H3K27me3/H3K4me2, we also report 14 distinct, lesser-known bi-, tri-, and tetravalent combinations of activating and repressive chromatin modifications, in platinum-resistant CP70 ovarian cancer cells. The vast majority (>90%) of all the histone marks studied localized to regions within 2000 bp of transcription start sites, supporting a role in gene regulation. Upon a simple alteration in the microenvironment, transition from two- to three-dimensional culture, an increase (17% to 38%) in repressive-only marked promoters was observed, concomitant with a decrease (31% to 21%) in multivalent (i.e., juxtaposed permissive and repressive histone marked) promoters. Like embryonic/tissue stem and other (non-ovarian) carcinoma cells, ovarian cancer cell epigenetic plasticity reflects an inherent transcriptional flexibility for context-responsive alterations in phenotype. It is possible that this plasticity could be therapeutically exploited for the management of this lethal gynecologic malignancy.

DNA methylation and histone modifications often function concomitantly to drive an aberrant program of gene expression in most cancers. Consequently, they have also been identified as being associated with ovarian cancer. However, several basic issues remain unclear - are these marks established early during normal ovarian functioning, or at a preneoplastic stage, or through a gradual accumulation, or do they arise de novo during transformation? Such issues have been difficult to address in ovarian cancer wherein preneoplastic lesions and progression models have not yet been established and drug-refractive disease progression is rapid and aggressive. The review presents an overview of the known involvement of histone modifications in various cellular states that might contribute to our understanding of epithelial ovarian cancer.

Silencing of tumor suppressor genes (TSGs), by DNA methylation, is well known in adult cancers. However, based on the "stem cell" theory of tumorigenesis, the early epigenetic events arising in malignant precursors remain unknown. A recent report demonstrates that, while pluripotent embryonic stem cells lack DNA methylation and possess a "bivalent" pattern of activating and repressive histone marks in numerous TSGs, analogous multipotent malignant cells derived from germ cell tumors (embryonic carcinoma cells) gain additional silencing modifications to those same genes. These results suggest a possible mechanism by which aberrant differentiation, mediated by histone and DNA methylation, instigates tumor progression.