A hormetic transcriptional program coregulates invasion, proliferation and dormancy to define metastatic potential.

Abstract

Metastasis remains the leading cause of cancer mortality, yet the factors that determine metastatic competence and the timing of its acquisition are not well understood. Using human breast cancer cohorts and multi-omics in preclinical models, here we show that cells exit the primary tumor with pre-set metastatic potential. Integrating spatial transcriptomics with single-cell gene expression and chromatin profiles, we identify the transcription factor Prrx1 as a master regulator of dissemination: beyond its known role in invasion, it represses proliferation by acting on cyclins and cell-cycle inhibitors (Ccnd1/2, Cdkn2a/b/c) and activates a dormancy program (Gas6, Mme, Ogn). Intermediate Prrx1 levels optimize the trade-off between invasion and proliferation/dormancy, producing a hormetic (nonlinear) relationship between Prrx1 expression and metastatic burden. Combined invasion and proliferation signatures strongly stratify breast cancer prognosis, underscoring the clinical relevance of this phenotypic interplay. These findings indicate that metastatic competence emerges from the integration of Prrx1 co-regulated molecular programs, explaining why some invasive cells enter dormancy while others resume growth.