Mechanical Homeostasis As a Determinant of Breast Cancer Metastatic Dormancy and Reactivation
Abstract
Purpose
Metastatic reactivation—the transition of dormant cancer cells into active, proliferative lesions—drives late cancer recurrence in many survivors. In breast cancer, up to 30% of patients develop distant metastases 5–25 years after achieving a disease-free state, effectively harboring a lifelong “metastatic time bomb.” This phenomenon raises fundamental questions: how metastatic tumor cells can remain dormant for decades, and what events trigger their reactivation. Using breast cancer as a model system, we aim to elucidate the mechanisms governing long-term metastatic dormancy and the processes that initiate metastatic reactivation.
Methods
We employ a mathematical modeling framework to test the hypothesis that mechanical homeostasis is a key mechanism underlying metastatic tumor dormancy, and to explore potential mechanisms of reactivation. In the model, disseminated metastatic tumor cells in distant organs are subject to two growth-suppressive mechanisms. First, mechanical forces exerted by surrounding normal tissue structures suppress tumor cell proliferation, motivated by observations that softening of the extracellular matrix facilitates metastatic growth and that both tumor and normal cells sense mechanical rigidity. Second, a diffusive biochemical signal from neighboring normal tissues limits the growth of both tumorous and normal cells. To account for the long and random waiting times before metastatic onset, we incorporate stochastic theory and formulate a chemical master equation describing metastatic dormancy.
Results
The model predicts the existence of two distinct states: a metastable dormant (growth-suppressed) state and an unbounded growth state. We identify an optimal transition path connecting these states, demonstrating that reactivation occurs through rare but large stochastic fluctuations that enable the system to cross a substantial entropic barrier.
Conclusion
This work provides a quantitative framework supporting the mechanical homeostasis hypothesis for metastatic dormancy and offers a mechanistic explanation for metastatic reactivation. Our results suggest that alterations in tissue mechanical properties can act as triggers for metastatic flare-ups.