Targeting RAB27A-mediated small extracellular vesicle secretion via CRISPR-Cas9 negatively affects proliferation and metastasis in both in vitro and in vivo SCLC models.

Small cell lung cancer (SCLC) comprises 15% of lung cancers with a capacity for early and distant metastatic development, high proliferative capacity, and poor survival rates. Ionizing radiation and chemotherapy are effective against early-stage SCLC. This sensitivity wanes over time, however, making treatment difficult. Different types of neoplasms have demonstrated the pivotal role of small extracellular vesicles (sEVs) in disease progression. However, the role of sEVs development in SCLC remains unclear. In this study, the impact of sEVs secretion in SCLC cells was investigated using the CRISPR-Cas9 system to target the RAB27A. The effects of sEVs release inhibition on tumour growth and metastasis were evaluated using micro-PET-CT analysis. A reduction in cellular proliferation as a consequence of sEVs release, along with diminished expression of proteins and RNA (CD9, CD63, and Tsg101) implicated in sEVs secretion in silenced SCLC cells (p < 0.001, p < 0.0001) was detected. The suppression of sEVs release exhibited significant adverse effects on tumor development and metastatic dissemination in the in vivo tumor model. The present study suggests that the targeting of RAB27A could be a viable cancer therapy for SCLC. Targeting the exosomal pathway has the potential to enhance treatment efficacy, and SCLC may depend on sEVs secretion.