Quenching Epigenetic Drug Resistance Using Antihypoxic Microparticles in Glioblastoma Patient-Derived Chips
Sewoom Baek1, Seung Eun Yu2, Yu-Heng Deng3
1Department of Brain Korea 21 FOUR Project for Medical Science, Medical Device Engineering and Management, Department of Medical Engineering, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
Abstract:
Glioblastoma (GBM) is one of the most intractable tumor types due to the progressive drug resistance upon tumor mass expansion. Incremental hypoxia inside the growing tumor mass drives epigenetic drug resistance by activating nongenetic repair of antiapoptotic DNA, which could be impaired by drug treatment. Hence, rescuing intertumor hypoxia by oxygen-generating microparticles may promote susceptibility to antitumor drugs. Moreover, a tumor-on-a-chip model enables user-specified alternation of clinic-derived samples. This study utilizes patient-derived glioblastoma tissue to generate cell spheroids with size variations in a 3D microchannel network chip (GBM chip). As the spheroid size increases, epigenetic drug resistance is promoted with inward hypoxia severance, as supported by the spheroid size-proportional expression of hypoxia-inducible factor-1a in the chip. Loading antihypoxia microparticles onto the spheroid surface significantly reduces drug resistance by silencing the expression of critical epigenetic factor, resulting in significantly decreased cell invasiveness. The results are confirmed in vitro using cell line and patient samples in the chip as well as chip implantation into a hypoxic hindlimb ischemia model in mice, which is an unprecedented approach in the field.
Insights
Oxygen microparticles combat drug resistance in glioblastoma (GBM) by reducing hypoxia. This approach enhances antitumor drug efficacy and decreases cancer cell invasiveness, offering a novel therapeutic strategy.
Area of Science:
- Oncology
- Biomedical Engineering
- Drug Delivery
Background:
- Glioblastoma (GBM) exhibits progressive drug resistance, particularly with tumor growth and increasing hypoxia.
- Hypoxia promotes epigenetic drug resistance by enabling DNA repair mechanisms that counteract anti-cancer treatments.
- Targeting tumor hypoxia is a potential strategy to re-sensitize GBM to therapies.
Purpose of the Study:
- To investigate the efficacy of oxygen-generating microparticles in overcoming hypoxia-driven drug resistance in glioblastoma.
- To utilize a patient-derived glioblastoma-on-a-chip model to study spheroid size-dependent drug resistance.
- To assess the impact of microparticle treatment on GBM cell invasiveness.
Main Methods:
- Generation of glioblastoma (GBM) spheroids of varying sizes within a 3D microchannel network chip using patient-derived tissue.
- Quantification of hypoxia-inducible factor-1a (HIF-1a) expression to correlate spheroid size with hypoxia.
- Treatment of spheroids with oxygen-generating microparticles and assessment of drug resistance and cell invasiveness.
- Validation in vitro using cell lines and patient samples, and in vivo using a mouse hindlimb ischemia model.
Main Results:
- Spheroid size positively correlated with hypoxia and epigenetic drug resistance, indicated by increased HIF-1a expression.
- Oxygen-generating microparticles significantly reduced drug resistance by downregulating key epigenetic factors.
- Treatment led to a marked decrease in glioblastoma cell invasiveness.
- The findings were consistent across in vitro models and an in vivo hypoxic environment.
Conclusions:
- Rescuing intratumoral hypoxia with oxygen-generating microparticles can overcome epigenetic drug resistance in glioblastoma.
- The GBM-on-a-chip model provides a valuable platform for studying tumor heterogeneity and drug response.
- This approach demonstrates potential for enhancing the effectiveness of anti-GBM therapies and reducing tumor spread.
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