Metastatic dissemination remains a principal determinant of outcome in epithelial cancers [1]. Beyond canonical biochemical signaling, accumulating evidence indicates that cell and nuclear mechanics regulate transcription-factor accessibility and thereby shape epithelial plasticity and invasive behavior [2], [3], [4]. Small GTPases orchestrate actin architecture, traction generation, and polarity during migration by integrating protrusion dynamics, stress-fiber contractility, and adhesion turnover to produce directed motility [5], [6]. Within this family, RhoB is well positioned to influence cytoskeletal remodeling and force transmission [7]; however, whether RhoB controls actin organization to nucleus-directed mechanotransduction that affects metastasis-relevant programs, and what specific role it plays in a mechanics-to-nucleus pathway, remains undefined.

Accordingly, we used colorectal epithelial cell lines as a phenotype- and measurement-tractable model system and compared transcriptomes under RhoB-competent and RhoB-deficient conditions. Enrichment analyses implicated epithelial-to-mesenchymal transition (EMT) and Wnt/β-catenin programs as differentially engaged according to RhoB status. Within this context, EMT is a key program associated with metastatic competence in epithelial systems [8], [9]. EMT entails loss of epithelial features, including apicobasal polarity and E-cadherin-mediated junctions, together with acquisition of mesenchymal phenotypes that enhance motility and invasiveness [8]. These changes occur alongside cytoskeletal remodeling and reduced cell rigidity that facilitate stromal invasion [10], [11]. Such characteristics position small-GTPase-controlled cytoskeletal and biomechanical states as plausible regulators of EMT plasticity [6]. Although previous work linked RhoB to metastasis and therapy resistance [12], [13], it remains unclear whether RhoB aligns cytoskeletal organization with nuclear mechanics to influence EMT programs.

To address this gap, we integrated genetic perturbations with quantitative cytoskeletal and nanomechanical measurements, subcellular localization assays, and functional migration and invasion assays in this epithelial model (Fig. 1a). Our results indicate that loss of RhoB is associated with attenuated F-actin polymerization, fewer stress fibers and lamellipodia, increased whole-cell and nuclear stiffness, reduced nuclear β-catenin accompanied by an epithelial shift in EMT markers, and diminished motility. We further identify Rab1A as a RhoB-associated small-GTPase-partner, with combined perturbation producing stronger effects than single-gene targeting. Together, these findings delineate a mechanics-to-nucleus route coordinated by a RhoB and Rab1A functional complex that links cytoskeletal organization to β-catenin compartmentalization and EMT-linked traits in an epithelial model system, suggesting principles for mechanically informed control of epithelial behavior.