Enhanced ASGR2 by microplastic exposure leads to resistance to therapy in gastric cancer

<b>Background:</b> Microplastics (MPs) are a new global environmental threat. Previously, we showed the biodistribution of MPs using [⁶⁴Cu] polystyrene (PS) and PET in mice. Here, we aimed to identify whether PS exposure has malignant effects on the stomach and induces resistance to therapy. <b>Methods:</b> BALB/c nude mice were fed 1.72 × 10⁴ particles/mL of MP. We investigated PS accumulation in the stomach using radioisotope-labeled and fluorescent-conjugated PS. Further, we evaluated whether PS exposure induced cancer stemness and multidrug resistance, and whether it affected tumor development, tumor growth, and survival rate <i>in vivo</i> using a 4-week PS-exposed NCI-N87 mouse model. Using RNA-Seq analysis, we analyzed whether PS exposure induced gene expression changes in gastric tissues of mice. <b>Results:</b> PET imaging results showed that a single dose of [⁶⁴Cu]-PS remained for 24 h in the mice stomach. The 4-week daily repetitive dose of fluorescent conjugated PS was deposited in the gastric tissues of mice. When PS was exposed, a 2.9-fold increase in migration rate was observed for NCI-N87 cells. Immunocytochemistry results showed decreased E-cadherin and increased N-cadherin expression, and flow cytometry, qPCR, and western blot analysis indicated a 1.9-fold increase in N-cadherin expression after PS exposure<b>.</b> Further, PS-induced multidrug resistance to bortezomib, paclitaxel, gefitinib, lapatinib, and trastuzumab was observed in the NCI-N87 mouse model due to upregulated CD44 expression. RNA-seq results identified increased asialoglycoprotein receptor 2 (<i>ASGR2</i>) expression after PS exposure, and <i>ASGR2</i> knockdown decreased cell proliferation, migration, invasion, and drug resistance. <b>Conclusion:</b> We demonstrated that <i>ASGR2</i> enhanced cancer hallmarks on PS exposure and induced resistance to chemo- and monoclonal antibody-therapy. Our preclinical findings may provide an incentive for further epidemiological studies on the role of MP exposure and its association with gastric cancer.