Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and resistant to conventional therapies, including chemo‐, radio‐, and immunotherapy. In this study, it is first determined that a combination of dihydroartemisinin (DHA) and RSL‐3 (a glutathione peroxidase 4 (GPX4) inhibitor) markedly induced ferroptosis of PDAC tumor cells. A mechanistic study revealed that DHA can react with iron ions to generate carbon radicals and deplete intracellular glutathione, thereby cumulatively triggering the lipid peroxidation of tumor cells with RSL‐3‐mediated GPX4 inhibition. A DHA‐conjugated amphiphilic copolymer is subsequently synthesized, and intracellular acidity and oxidation dual‐responsive DHA nanoparticles are further engineered for the tumor‐specific co‐delivery of DHA and RSL‐3. The resultant nanoparticles (PDBA@RSL‐3) efficiently induce ferroptosis of tumor cells in the Panc02 tumor‐bearing immune‐deficient mouse model, and elicit T‐cell‐based antitumor immunity in the immune‐competent mouse model. The combination of PDBA@RSL‐3 nanoparticles and programmed death ligand 1 blockade therapy efficiently inhibits PDAC tumor growth in the immune‐competent mouse models. This study may provide novel insights for treatment of PDAC with ferroptosis‐based immunotherapy.
Anaplastic thyroid carcinoma (ATC) is aggressive and lethal with extrathyroidal invasion, distant metastasis, and resistance to conventional therapies. Cancer stem cells (CSCs) are proposed to be responsible for high recurrence rate in ATC. MicroRNAs (miRNAs) have recently been found as an important class of cellular regulators of ATC carcinogenesis. Identification of CSC-related miRNAs and targets is therefore a priority for the development of new therapeutic paradigms. Patient-derived ATC cells were cultured in conditional media on poly-hema-treated dish. ATC CSCs were isolated and enriched through as a series of steps including initial isolation of sphere-forming CSC population, subsequent amplification of this CSC population in a xenograft model treated with cisplatin, and purification of CSCs from xenograft tumors followed by final enrichment using sphere-forming assays. Expression of CSC markers was measured by flow cytometry, immunofluorescence staining, qPCR and western blot analyses. Expression of miRNAs in ATC-CSCs was profiled by microarray analysis. Proliferation and differentiation rates were determined based on the size of spheres formed in vitro and tumors formed in vivo. We successfully isolated and enriched an ATC-CSC population. We identified 17 miRNAs differentially expressed in primary ATC cells vs. ATC-CSCs, among which miRNA-148a was significantly downregulated in ATC-CSCs. Overexpression of miRNA148a in ATC-CSCs induced cell cycle arrest and loss of stem cell characteristics. In addition, we identified INO80 as a target gene of miR-148a. The expression of INO80 was upregulated in ATC-CSCs and downregulated upon miRNA-148 overexpression. Overexpression of miRNA-148a and knockdown of INO80 acted synergistically to decrease the expression of stem cell marker genes as well as to attenuate stem cell-specific properties including the ability to form tumors. This study identified novel contrasting roles for miR-148a and INO80 in the regulation of the stemness of ATC-CSCs and their capacity to initiate tumor formation. Our findings may open a new avenue for therapeutic development against ATC that targets INO80 in the CSCs through enhancing miRNA-148a levels.
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