Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of B-cell malignancies but have not yet succeeded in acute myeloid leukemia (AML), largely due to the lack of cell surface antigens that can distinguish leukemia cells from essential normal hematopoietic stem cells (HSCs). Here, we used a newly developed high-affinity monoclonal antibody (mAb) B16, which is specific for the surface ROR2 in both human and mouse. Although ROR2 is a developmentally restricted protein that is primarily expressed during embryogenesis, we find that ROR2 protein is generally expressed by AML cells, including leukemia stem cells (LSCs), in patients with adverse-risk disease. Consistently, ROR2 is undetectable in most normal postnatal tissues and HSCs. Additionally, ROR2 can activate STAT3 signaling in response to Wnt11 in AML. Employing the binding domain of the anti-ROR2 mAb, we generated anti-ROR2 CAR T cells that selectively eliminated ROR2-positive AML cells of these patients while sparing normal HSCs. Intravenous infusion of such anti-ROR2 CAR T cells into immune-deficient mice selectively eradicated engrafted ROR2-positive human AML cells, including LSCs, without adversely affecting non-neoplastic normal mouse tissues or hematopoiesis. We propose that anti-ROR2 CAR T cells may offer therapeutic benefit for AML patients.
Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. In cancer, metabolic reprogramming is characterized by enhanced iron uptake, altered lipid metabolism, and sustained oxidative stress, creating a paradoxical state that increases vulnerability to ferroptosis while simultaneously activating antioxidant defense systems to sustain survival. Therefore, identifying and characterizing key regulators of pro-ferroptotic and anti-ferroptotic pathways is essential for precise modulation of ferroptosis sensitivity in cancer therapy. Circular RNAs (circRNAs) have emerged as important regulators of the ferroptosis network. Recent evidence indicates that circRNAs coordinate iron metabolism, lipid remodeling, redox balance, and stress-responsive signaling, thereby influencing tumor progression, stemness maintenance, immune adaptation, and therapy resistance. This review summarizes circRNA-mediated regulation of ferroptosis and highlights its mechanistic significance and translational potential in cancer.
The astounding success of mRNA empowers the diverse application of mRNA therapeutics in multiple genetic disorders. Besides the vaccines, the rational design of mRNA drugs has been explored widely to target the undruggable gene therapy for managing cancer. Restoration of the p53 tumor suppressor gene via introducing foreign p53-mRNA therapeutics may inhibit the growth and development of tumors. Since the development of mRNA transporting vehicles, liposome-based nanoparticles are the mainstay and are widely used in several ex vivo and clinical studies. But the delivery of mRNA outside the immune cells and hepatocytes for protein replacement therapy through systemic administartion is very limited and requires additional optimization. Here, we modified classical LNP (lipid nanoparticles) with SSNs (strontium sulfite nanoparticles) and complexed the LNP with p53 mRNA to improve the delivery efficiency of p53 mRNA. We assumed that restoration of p53 function in breast tumor cells might improve antitumor efficacy against breast cancer. We screened the SSNs-LNP to get the favorable physicochemical properties and to improve the delivery efficiency. The SSNs-LNP showed a threefold increase of luciferase gene expression in breast cancer cell lines compared to the classical LNP. In the animal model, the SSNs-LNP improved the biological stability and tumor targeting efficiency and restored the expression of p53, resulting in a significant reduction of tumor volume. Thus, we anticipate that the hybrid SSNs-LNP particles could be a translatable nanocarrier system in transporting mRNA drugs for the treatment of cancers.
Laryngeal carcinoma (LC) remains a challenging malignancy with poor prognosis, necessitating the identification of novel therapeutic targets. This study investigates the functional role and underlying mechanism of the extracellular matrix protein Laminin Subunit Beta-3 (LAMB3) in LC progression. Bioinformatics analysis of multiple GEO datasets demonstrated that LAMB3 is significantly overexpressed in LC tissues and that high LAMB3 expression correlates with reduced overall survival in patients. Functional validation using two distinct LC cell lines revealed that knockdown of LAMB3 potently suppresses cellular proliferation, migration, clonogenic capacity, and glycolytic metabolism in vitro, and inhibits tumor growth in xenograft models. Mechanistically, we identified that LAMB3 activates the EGFR-MAPK signaling axis, increasing the phosphorylation of EGFR and ERK, leading to transcriptional upregulation of the key glycolytic enzyme PKM, resulting in enhanced glycolytic flux, as evidenced by increased glucose uptake and lactate production. Critically, the oncogenic effects of LAMB3 are entirely dependent on this axis; both genetic silencing of PKM and pharmacological inhibition of the EGFR or MAPK abrogate LAMB3-driven glycolytic reprogramming and tumor-promoting phenotypes in vitro and in vivo. Our findings establish LAMB3 as a novel prognostic biomarker and reveal the LAMB3-EGFR-MAPK-PKM signaling axis as a promising therapeutic target for intervention in laryngeal carcinoma.
Epithelial ovarian cancer (EOC) is characterized by high mortality, insidious onset, and pronounced heterogeneity, underscoring the critical need for effective biomarkers for early detection and subtype-specific diagnosis. While DNA methylation represents a stable epigenetic marker, prior studies have largely relied on profiling techniques with limited genomic coverage and have often overlooked subtype-specific differences essential for guiding treatment decisions. To address this, we performed whole-genome bisulfite sequencing on 44 normal ovarian tissues and 89 EOC tissues encompassing all five histological subtypes, integrated with transcriptome sequencing, to comprehensively evaluate the diagnostic and prognostic utility of DNA methylation across EOC subtypes. Our analyses revealed that genome-wide methylation profiles effectively distinguished normal from tumor tissues and captured the substantial heterogeneity inherent to EOC. Differentially methylated regions (DMRs) and differentially expressed genes were enriched in immune-related processes and epithelial differentiation, aligning with the increased proportions of epithelial and immune cells identified through deconvolution analysis. Subtype-specific DMRs further implicated hormonal pathways in endometrioid (EC) and clear cell (CCOC) carcinomas, and linked mucinous ovarian cancer (MOC) to fluid regulation. Integrative analysis of DMRs and cellular composition indicated that epithelial cells in high-grade serous (HG), low-grade serous (LG), and EC tumors most closely resembled fallopian tube, ovarian, and endometrial epithelial cells, respectively, whereas MOC and CCOC epithelial cells showed similarity to gastrointestinal and renal epithelia. Moreover, weighted gene co-expression network analysis identified epithelia-associated DMRs that achieved up to 90% specificity for subtype classification in internal validation and demonstrated prognostic relevance in independent public datasets. In conclusion, the subtype-specific DNA methylation markers identified in this study accurately reflect the distinct histological features of each EOC subtype and hold promise for application in subtype classification and prognosis prediction, thereby providing a scientific foundation for future clinical interventions in EOC.
