ARID1A loss induces P4HB to activate fibroblasts to support lung cancer cell growth, invasion, and chemoresistance

Loss of AT‐interacting domain‐rich protein 1A (ARID1A) frequently occurs in human malignancies including lung cancer. The biological consequence of ARID1A mutation in lung cancer is not fully understood. This study was designed to determine the effect of ARID1A‐depleted lung cancer cells on fibroblast activation. Conditioned media was collected from ARID1A‐depleted lung cancer cells and employed to treat lung fibroblasts. The proliferation and migration of lung fibroblasts were investigated. The secretory genes were profiled in lung cancer cells upon ARID1A knockdown. Antibody‐based neutralization was utilized to confirm their role in mediating the cross‐talk between lung cancer cells and fibroblasts. NOD‐SCID‐IL2RgammaC‐null (NSG) mice received tumor tissues from patients with ARID1A‐mutated lung cancer to establish patient‐derived xenograft (PDX) models. Notably, ARID1A‐depleted lung cancer cells promoted the proliferation and migration of lung fibroblasts. Mechanistically, ARID1A depletion augmented the expression and secretion of prolyl 4‐hydroxylase beta (P4HB) in lung cancer cells, which induced the activation of lung fibroblasts through the β‐catenin signaling pathway. P4HB‐activated lung fibroblasts promoted the proliferation, invasion, and chemoresistance in lung cancer cells. Neutralizing P4HB hampered the tumor growth and increased cisplatin cytotoxic efficacy in two PDX models. Serum P4HB levels were higher in ARID1A‐mutated lung cancer patients than in healthy controls. Moreover, increased serum levels of P4HB were significantly associated with lung cancer metastasis. Together, our work indicates a pivotal role for P4HB in orchestrating the cross‐talk between ARID1A‐mutated cancer cells and cancer‐associated fibroblasts during lung cancer progression. P4HB may represent a promising target for improving lung cancer treatment.

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