Aug 2026· Frontiers in Oncology· Vol 16· 0 citations· 149 references
Medicine
TL;DR
The conceptual boundaries and operational criteria for identifying OnF in CRC are discussed, its regulatory mechanisms, plasticity-associated phenotypes, and translational relevance are examined, and the importance of distinguishing direct evidence of OnF from evidence of related plasticity mechanisms is emphasized.
Abstract
Colorectal cancer (CRC) progression and metastasis, as well as tolerance to therapy, are driven not only by genetic alterations but also by cell-state plasticity. Oncofetal reprogramming (OnF) refers to the reactivation of fetal intestinal developmental or injury-repair programs in tumor cells, thereby weakening adult lineage identity and enhancing the capacity for state transitions. Available evidence suggests that, in specific Wnt-dependent or APC-aberrant contexts, YAP/TAZ–TEAD and AP-1 may act cooperatively to establish and maintain the OnF state, whereas Wnt, EGFR–MAPK, FGF/FGFR, TGF-β, and extracellular matrix signaling contribute to its establishment and maintenance in a context-dependent manner. The OnF state can also intersect with epithelial–mesenchymal plasticity, dynamic stemness, drug-tolerant persister states, and immune and stromal niches, collectively increasing cellular heterogeneity, adaptability to therapy, and relapse potential in CRC. This review discusses the conceptual boundaries and operational criteria for identifying OnF in CRC, examines its regulatory mechanisms, plasticity-associated phenotypes, and translational relevance, and emphasizes the importance of distinguishing direct evidence of OnF from evidence of related plasticity mechanisms. Further elucidation of the OnF state may facilitate biomarker development and anti-plasticity therapies, although its clinical translation will require standardized state classification and clinical validation.
Hepatocellular carcinoma (HCC) remains a major global health burden, with therapeutic resistance limiting the long-term efficacy of current treatments. Although cancer stem cell (CSC) models have been proposed to explain tumor initiation and relapse, strategies targeting marker-defined CSC populations have shown limited clinical benefit. Increasing evidence indicates that stemness in HCC is not a fixed cellular trait but a dynamic and reversible state that can be induced, maintained, and re-established under therapeutic pressure. This stemness plasticity is regulated by tumor-intrinsic signaling pathways, including TGF-β, YAP/TAZ, and Wnt/β-catenin, and stabilized by epigenetic and post-transcriptional mechanisms such as N6-methyladenosine (m6A) modification. In parallel, spatially organized tumor microenvironmental niches composed of cancer-associated fibroblasts, macrophages, and endothelial cells provide critical signals that support stem-like phenotypes and immune evasion. These interconnected mechanisms collectively contribute to therapeutic resistance and tumor progression. This review synthesizes current evidence linking stemness plasticity to spatial niche regulation and treatment failure in HCC, and outlines a therapeutic framework that integrates targeting of intracellular regulatory programs with disruption of microenvironmental support systems. We further discuss the implications of this framework for the development of combination strategies and dynamic biomarkers that better capture the context-dependent nature of stemness. Together, these insights support a shift from targeting static cell populations toward targeting the regulatory processes that govern tumor cell plasticity in HCC.
H. Ahn, Sujin Kim, H. Cho· Journal of Liver Cancer· 0 citations
It is argued that metastatic competence, therapy resistance, and immune evasion can be viewed as functional outputs of remembered plasticity rather than solely as consequences of a contemporaneous mesenchymal phenotype, positioning memory-bearing states as an important target for future therapeutic strategies.
Dominika Denisz, Magdalena Fabian, Jan Olszewski et al.· Cellular Oncology· 0 citations
Tumor plasticity and microenvironmental heterogeneity are established as an integrated, evolving system that fuels metastasis and limits durable treatment responses.
G. Dagar, M. Dagar, Ashna Gupta et al.· MedComm· 0 citations
Cancer stem cells (CSCs) drive therapeutic resistance, metastasis, and tumor recurrence through reversible transitions among stem-like, differentiated, epithelial, and mesenchymal states, which are sustained by interconnected epigenetic mechanisms. To our knowledge, this is the first review to integrate curcumin-mediated regulation of DNA methylation, chromatin remodeling, and non-coding RNAs within a single CSC plasticity framework and to propose the concept of an “epigenetic collapse of CSC plasticity” as a mechanistic explanation for how curcumin may weaken stemness, state switching, and adaptive treatment resistance. Evidence was critically evaluated through structured searches of PubMed/MEDLINE, Scopus, Web of Science Core Collection, Google Scholar, and citation tracking, while direct curcumin–epigenetic evidence was distinguished from independent CSC evidence and inferential mechanistic links. Curcumin has been reported to modulate DNMT1 and locus-specific DNA methylation; regulate HDACs, p300/CBP, EZH2, H3K27me3, and BMI1; and alter selected microRNA, long non-coding RNA, and circular RNA pathways, with comparatively stronger evidence involving the miR-34 family, miR-200c, miR-21, H19, and circHN1. However, current evidence is constrained by the predominance of bulk cancer-cell models, heterogeneous formulations and exposure conditions, and the scarcity of epigenetic rescue experiments combined with rigorous functional CSC assays. By unifying previously fragmented epigenetic evidence, this review advances a new evidence-weighted model in which curcumin may suppress CSC persistence not through a single molecular target, but by destabilizing the multilayer epigenetic circuitry that enables plasticity. Curcumin should therefore be regarded as a context-dependent, multilayer epigenetic modulator rather than an established CSC-eradicating therapy, and its translational relevance requires validation in prospectively defined CSC models with pharmacologically justified delivery and exposure conditions.
J. N. Rana, Jayashri Ghosh, Shoail Mumtaz· International Journal of Mol...· 0 citations
This review evaluating how the antagonistic interplay between Polycomb and Trithorax complexes, chromatin modifier activity, and enhancer reprogramming affects lineage identity and enables multi-lineage plasticity in cancer underscores epigenetic deregulation as a primary driver of lineage plasticity and intratumoral heterogeneity.
Ezgi Boyvatlı, Burcu Akman, E. Bağırsakçı et al.· FEBS Letters· 0 citations
Epigenetics plays a central role in cancer development and progression by governing the expression of genes involved in these processes. Accumulating evidence strongly indicates that these mechanisms not only alter cancer cell‐intrinsic properties but also mediate reciprocal interactions between cancer cells and the tumor microenvironment (TME). In the context of cancer cell‐intrinsic changes, epigenetic alterations contribute to cancer cell plasticity by regulating stemness, cell state transitions, and therapy resistance. In addition, epigenetic changes are a key driver of the establishment of a tumor‐supportive environment by modifying the states of TME components, including fibroblasts, macrophages, and myeloid‐derived suppressor cells. Epigenetic reprogramming in cancer cells and TME components is often induced by factors such as hypoxia and the secretion of exosomal long noncoding RNAs (lncRNAs), cytokines, and metabolites. In this review, we discuss various epigenetic mechanisms controlling cancer cell‐intrinsic states, cancer cell–TME crosstalk, current epigenetic therapies, and future research directions that may lead to the discovery of new biomarkers and the development of effective epigenetic anticancer therapeutics.
Ji Hoon Park, Mi-Young Kim· Molecular Oncology· 0 citations
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