EZH2 inhibition in mesothelioma cells increases the release of extracellular vesicles that skew neutrophils toward a pro-tumor phenotype.

ABSTRACT: BAP1-deficient pleural mesotheliomas have been shown to be sensitive to inhibition of the histone methyltransferase EZH2 in preclinical settings but only showed modest efficacy in clinical trials. We recently demonstrated that in BAP1-proficient mesothelioma cells, CDKN2A plays a crucial role in response to the selective EZH2 inhibitor tazemetostat. Therefore, in the current study, we employed a quantitative proteomic mass spectrometry approach to analyze changes in protein expression in response to tazemetostat in BAP1-CDKN2A proficient MSTO-211H cells cultured as spheroids. Our results demonstrate that tazemetostat treatment induced an increase in the expression of 21 proteins and a decrease in the expression of 12 proteins. Notably, RAB27b and CD63 were among the most up-regulated proteins. We also demonstrate that higher levels of RAB27b and CD63 were linked to a heightened release of extracellular vesicles (EVs). When exploring the impact of tumor-derived EVs on naïve neutrophil behavior, we found that brief exposure to EVs derived from tazemetostat-treated cells skewed naïve neutrophils toward a pro-tumor phenotype characterized by high levels of PD-L1 and mesothelin surface expression. These EV-elicited neutrophils suppressed lymphocyte proliferation while enhancing tumor cell growth. Interestingly, most up-regulated proteins in EV cargo derived from tazemetostat-treated spheroids were FZD6, the catalytic subunit alpha of PI3K and PPAR-α, while the most downregulated was ENOX2.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pleural Mesothelioma Cell

DISEASE(S): Malignant Mesothelioma

SUBMITTER: Marcello Manfredi  

LAB HEAD: Marcello Manfredi

PROVIDER: PXD057566 | Pride | 2025-11-24

REPOSITORIES: Pride