Phase separation of PHLDB2 promotes lung adenocarcinoma progression through FLNA stabilization and ERK activation

Abstract

Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer, but the phase separation-related mechanisms that support its progression remain poorly defined. By integrating phase separation-related gene profiling with prognostic modeling, we identified PHLDB2 as a high-risk candidate associated with poor outcome in LUAD. PHLDB2 protein expression was elevated in LUAD tissues and patient-derived tumor organoids and showed predominant cytoplasmic punctate localization. Recombinant protein assays, live-cell imaging and FRAP analysis demonstrated that PHLDB2 forms dynamic condensates through its intrinsically disordered regions. Functionally, PHLDB2 depletion suppressed adhesion-associated signaling programs and reduced LUAD cell adhesion, migration, invasion, proliferation, and xenograft tumor growth. Conversely, full-length PHLDB2 enhanced these cellular and tumor-associated effects, whereas these effects were attenuated in cells expressing IDR-deletion variants. Mechanistically, PHLDB2 colocalized and co-assembled with FLNA in condensate-like structures and was associated with increased FLNA protein stability and ERK phosphorylation. FLNA restoration partially rescued ERK activation and proliferation after PHLDB2 knockdown. These findings identify PHLDB2 as a phase separation-associated regulator of LUAD progression and suggest that it promotes malignant phenotypes partly through the FLNA-ERK signaling axis.