Nanoparticle enhanced combination therapy for stem-like progenitors defined by single-cell transcriptomics in chemotherapy-resistant osteosarcoma

Abstract

The adaptation of osteosarcoma cells to therapeutic pressure impedes the efficacy of chemotherapy for osteosarcoma. However, the characteristics and cellular organization of therapy-resistant cells in osteosarcoma tumors remain elusive. Here, we utilized single-cell transcriptomics to systematically map the cell-type-specific gene expression in a chemotherapy-resistant osteosarcoma tumor. Our data demonstrated the VEGFR2-JMJD3-abundant subsets as quiescent stem-like cells, thereby establishing the hierarchy of therapy-resistant actively cycling progenitor pools (JMJD3-abundant) in osteosarcoma. VEGFR2 inhibitor and JMJD3 inhibitor synergistically impeded osteosarcoma cell propagation and tumor growth. Although osteosarcoma cells are predisposed to apoptosis induced by the synergistic therapy through activation of the CHOP pro-apoptotic factor via the endoplasmic reticulum (ER) stress, the stem-like/progenitor cells exhibit an adaptive response, leading to their survival. Reduction in cellular glutathione levels in stem-like/progenitor cells caused by the treatment with a glutathione synthesis inhibitor increases ER stress-induced apoptosis. Importantly, the marked therapeutic improvement of synergistic therapy against stem-like/progenitor cells was achieved by using glutathione-scavenging nanoparticles, which can load and release the drug pair effectively. Overall, our study provides a framework for understanding glutathione signaling as one of the therapeutic vulnerabilities of stem-like/progenitor cells. Broadly, these findings revealed a promising arsenal by encapsulating glutathione-scavenging nanoparticles with co-targeting VEGFR2 and JMJD3 to eradicate chemotherapy-resistant osteosarcoma.

Chondrocyte-derived Exosomal miR-195 Inhibits Osteosarcoma Cell Proliferation and Anti-Apoptotic by Targeting KIF4A in vitro and in vivo

“…Because of the limitations in diagnosis and treatment, approximately 30% of patients are still prone to lung metastases with poor prognosis and high mortality [24] . Currently, a combination of surgery and chemotherapy is the primary means of treating OS [25] . However, the prognostic treatment outcome has not improved greatly in recent years, and the emergence of resistance is an important contributing factor [26] .…”

Active Targeting Nanoparticle Self‐Assembled from Cisplatin‐Palbociclib Amphiphiles Ensures Optimal Drug Ratio for Combinatorial Chemotherapy

“…This might be attributed to the rapid excretion of small molecule by liver and spleen. [ 32 ] As time prolonging to 24 h, the fluorescence of tumor site gradually increased and could be distinguished from other tissues in PEG‐PCN and iRGD‐PCN group (Figure 5D). Furthermore, the fluorescence intensity in major organs and tumor sites was quantified in ex vivo imaging (Figure 5E,F).…”

Oxidative and Antioxidative Status Expressed as OSI Index and GSH/GSSG Ratio in Children with Bone Tumors after Anticancer Therapy Completion

“…According to these authors, the metabolomics data indicated that both the citrate cycle (TCA) and glutathione metabolism were downregulated (elevation of GSSG levels) in human osteosarcoma cell line as a result of a decline in mitochondrial metabolism. However, Wang et al [ 42 ] found that osteosarcoma stem-like/progenitor cells adapted to gain a survival advantage by enhanced GSH synthesis due to the maintenance of resistance to endoplasmic reticulum stress-induced apoptosis. γ-Glutamylcyclotransferase in the γ-glutamyl cycle may play an important role in regulating the synthesis of glutathione by limiting the availability of γ-glutamylcysteine (γ-Glu-Cys) [ 43 ].…”