One of the most profound insights from scRNA-seq studies is the plasticity of cancer cells—their ability to switch phenotype to adapt to any hostile environment or evade immune surveillance.
Cancer cells transition between different states: from cancer stem cells to differentiated states
Cancer stem cells (CSCs) are a pluripotent subpopulation capable of self-renewal and generating the full spectrum of tumor cell types, making them the quintessential model of tumor plasticity. In normal tissues, pathways such as Wnt maintain stemness, guide development, and ensure tissue homeostasis. Mutations in key regulators (e.g., APC, AXIN, CTNNB1) can overactivate Wnt signaling, promoting uncontrolled proliferation, enhanced survival, and malignant transformation.
CSC differentiate in tumor cells, responsible for its growth and metastasis. Differentiation can be promoted by the TME, but can transdifferentiate into structures supporting the tumor growth, like endothelial-like cells to support angiogenesis, tumor growth and metastasis (angiogenic mimicry), or stromal or mesenchymal lineages that will support growth and metastasis.
Intermediate or transitional states that cancer cells undergo during the process of metastasis or in response to treatment
Plasticity extends beyond CSCs to other cells. Often these are transitional states associated with metastasis.
The epithelial to mesenchymal transition (EMT) for instance is a normal process in embryonic development, wound repair and cell motility. The tumor uses these characteristics to confer them an aggressive and metastatic feature. In the TME, epithelial cells often exhibit hybrid states co-expressing epithelial and mesenchymal markers. EMT is orchestrated by transcription factors such as Snail, ZEB, Twist, and LEF-1, which repress epithelial genes and activate mesenchymal programs.
Transcriptomic and epigenetic mechanisms driving cancer cell state plasticity
Cancer plasticity emerges from a network of genetic, transcriptional, and epigenetic mechanisms.
Transcriptional reprogramming refers to dynamic shifts in gene expression, often mediated by Wnt, Notch, and receptor tyrosine kinase pathways, allowing rapid phenotype switching. For example, the Notch signaling pathway induces the expression of the transcription factor Slug which represses the expression of the adhesion molecule E-Cadherin, initiating the transition.
Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs—regulate cancer cell plasticity without altering the underlying DNA sequence.
Dynamic histone modifications (e.g., acetylation, methylation) can restructure chromatin, modulating DNA accessibility to transcription factors and thereby shaping gene expression programs.
In cancer, abnormal DNA methylation patterns frequently silence tumor suppressor genes or activate oncogenes, driving progression and enhancing plasticity. Changes in chromatin architecture, often mediated by ATP-dependent remodeling complexes such as SWI/SNF, further influence the transcriptional states and enable lineage transitions.
TLDR: Tumor cells are not locked into fixed identities. In response to stress, environmental cues, and treatment, they can transition between phenotypic states, enabling survival, invasion, and resistance. These shifts include the adoption of stem-like, mesenchymal, or lineage-ambiguous transcriptional programs that support aggressive behavior. Plasticity allows tumors to adapt rapidly to changing conditions and undermines durable therapeutic control. Single cell RNA sequencing captures these dynamic state transitions, revealing how flexible cell identities fuel progression, metastasis, and treatment resistance.
