Cancer Dormancy: a Dynamic Equilibrium Between the Epigenome, Inflammation, and Tumor Vulnerability
Tumor dormancy is a condition in which disseminated tumor cells or micrometastases remain in a quiescent state for years or even decades, escaping treatments and immune surveillance. This is not a simple halt in proliferation, but a dynamic equilibrium in which metabolism, immunity, and epigenetic regulation interact to keep the cell silent yet viable.
At LETE, we approach dormancy as a complex regulatory phenomenon shaped by the exposome and modulated by epigenetic processes that determine whether a cell remains quiescent, reactivates, or evolves toward more aggressive phenotypes.
Dormancy as an Adaptive State: Metabolism, Stress, and Epigenetic Control
Dormant cells display a distinctive profile: low replicative stress, reduced energetic metabolism, a highly stable epigenetic configuration, and finely tuned immune interactions. This state enables survival in hostile microenvironments but also makes dormancy sensitive to systemic perturbations such as chronic inflammation, oxidative stress, metabolic dysfunction, and shifts in stromal signaling.
Biological aging, loss of homeostatic capacity, and adverse environmental exposures progressively weaken this equilibrium. Epigenetic deregulation, in particular, plays a key role in facilitating the exit from dormancy.
Transposable Elements and Epigenetic Instability: Early Signals of Reactivation
A central component of our work focuses on repeated genomic elements—especially LINE and HERV families—which constitute a substantial proportion of the genome and act as sensors of epigenetic and metabolic stress. Their high methylation levels promote heterochromatin formation and transcriptional stability.
When chronic inflammation, oxidative stress, or reduced availability of key epigenetic cofactors (such as SAM, NADPH, or GSH) compromise this silencing, transposable elements can:
- trigger viral-like inflammatory responses
- increase transcriptional noise
- interfere with chromatin compaction
- destabilize 3D regulatory networks
These events can facilitate the transition from a dormant to a proliferative state, particularly in conditions of accelerated aging or unfavorable exposome profiles.
Inflammation and Exit from Dormancy: an Integrated Exposome – Epigenome – Phenotype System
Reactivation of dormant tumor cells does not result from a single signal but from the integration of:
- persistent low-grade inflammation
- metabolic alterations (lipids, glucose, mitochondrial stress)
- loss of epigenetic control over transposable elements
- microenvironmental changes that favor proliferation
These layers interact synergistically and create conditions conducive to reawakening. Our work shows that global methylation of repeated elements modulates sensitivity to inflammatory signals, acting as an effect modifier that shapes susceptibility to dormancy escape.
LETE’s Contribution: an Integrative Model Connecting Omics, Exposome, and Adaptive Processes
At LETE, we study dormancy through a multi-level framework that combines:
- epigenomics (methylation, chromatin, TEs)
- inflammatory and metabolic profiling
- extracellular vesicle–mediated signaling
- biological aging metrics
- environmental and lifestyle exposures
- interpretable statistical modeling and sustainable machine learning
We are particularly interested in interventions that can strengthen the dormant state. For example, preoperative physical activity in breast cancer patients (PhActHealth) modulates systemic inflammation, metabolism, and the vulnerability of disseminated cells.