Chronically Established ρ0 Cancer Cells Exhibit Shared Stemness-Associated and Aggressive Phenotypes Across Multiple Cancer Cell Lines.

Abstract

Chronically established mitochondrial DNA-depleted (ρ⁰) cancer cells may exhibit phenotypic changes beyond metabolic dysfunction; however, whether such changes are shared across different cancer types remains unclear. In this study, we generated chronically established ρ⁰ models from pancreatic, lung, and breast cancer cell lines and examined their common phenotypic features. Compared with their parental wild-type counterparts, the ρ⁰ cell lines exhibited increased proliferation, chemoresistance-related features, sphere-forming ability, wound closure, invasion-related phenotypes, and angiogenic activity, together with common morphological alterations. These changes were accompanied by VDAC1 upregulation and cytoskeletal remodeling. Pharmacologic treatment with VBIT-4 attenuated several of these phenotypes, whereas its effects on chemoresistance-related responses varied across cell lines. Collectively, these findings suggest that chronically established ρ⁰ cancer cells exhibit shared stemness-associated and aggressive phenotypes across multiple cancer cell lines, accompanied by VDAC1 upregulation and cytoskeletal remodeling.