CD133⁺ Vesicles Mediate Resistance to RAS-ERK Inhibition Regulated by YAP Activation in Liver Cancer Cells

CD133, a pentaspan plasma membrane protein, has been viewed as a biomarker of stem cells in normal and cancer tissues, although its function and mechanism are unclear. In previous studies, we identified a new type of CD133 + intracellular vesicles, named intercellsome, which is implicated in direct cell-cell communication under stress conditions. However, the regulatory mechanism and biological significance of these CD133 + vesicles are largely unknown, highlighting a gap in understanding of this cellular communication mechanism. We show here that CD133 acts as a stress response marker in cancer cells, with its expression and vesicle formation significantly induced under MEK inhibitor-mediated proliferative stress. The CD133 + vesicles are essential for maintaining cell proliferation under stress conditions in vitro . Mechanistically, the MEKi activates the Hippo-YAP signaling pathway, which promotes CD133 transcription, establishing a novel connection between YAP signaling and CD133 + vesicle biogenesis. Further, CD133 plays a critical role in YAP-driven liver cancer progression in mice. This study defines a critical role of CD133 + vesicles in stress response regulated by YAP, which advances the understanding of CD133 functions beyond its stem cell-associated roles and suggests new avenues for therapeutic intervention of liver cancer relapse.