Nanoparticle enhanced combination therapy for stem-like progenitors defined by single-cell transcriptomics in...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Osteosarcoma chemotherapy resistance poses a significant clinical challenge.
• The cellular organization and characteristics of therapy-resistant osteosarcoma cells are not well understood.

Purpose of the Study:

• To characterize gene expression in chemotherapy-resistant osteosarcoma cells using single-cell transcriptomics.
• To identify therapeutic vulnerabilities in resistant osteosarcoma stem-like/progenitor cells.

Main Methods:

• Single-cell transcriptomics to map gene expression in resistant osteosarcoma.
• Inhibition of VEGFR2 and JMJD3 pathways.
• Assessment of endoplasmic reticulum (ER) stress and glutathione levels.
• Utilized glutathione-scavenging nanoparticles for drug delivery.

Main Results:

• Identified quiescent stem-like cells (VEGFR2-JMJD3-abundant) and actively cycling progenitor pools in resistant osteosarcoma.
• Combined VEGFR2 and JMJD3 inhibition synergistically reduced tumor growth.
• Stem-like/progenitor cells survived synergistic therapy via adaptive responses.
• Reducing glutathione levels enhanced ER stress-induced apoptosis in stem-like/progenitor cells.
• Glutathione-scavenging nanoparticles loaded with VEGFR2 and JMJD3 inhibitors improved therapeutic outcomes.

Conclusions:

• Glutathione signaling represents a therapeutic vulnerability in osteosarcoma stem-like/progenitor cells.
• Co-targeting VEGFR2 and JMJD3 with glutathione-scavenging nanoparticles is a promising strategy for eradicating chemotherapy-resistant osteosarcoma.