Cellular Oncology最新文献

Purpose: Anaplastic thyroid cancer (ATC) is a rare but aggressive malignancy with unmet clinical needs for novel therapeutic agents. Most prior studies have relied on limited ATC cell lines, which fail to recapitulate tumor heterogeneity. This study aimed to discover novel agent for ATC via patient-derived organoid (PDO)-based drug screening and investigate the underlying therapeutic mechanism.

Methods: Drug screening was performed on ATC organoids using a drug library of stem cell differentiation compounds. RNA-sequencing identified pathway-level mechanisms, while structure-based molecular docking prioritized target proteins.

Results: Using a library of stem cell differentiation compounds, we identified homoharringtonine (HHT) as a potent inhibitor for ATC growth in vitro and in vivo. Mechanistically, this effect was mediated by lysosomal dysfunction, which blocked autophagosome-lysosome fusion and triggered cytotoxicity. Furthermore, HHT exhibited high affinity for the PI3K p110 subunit, activating the PI3K-AKT-mTOR pathway to phosphorylate transcription factor EB, retaining it in the cytoplasm and thereby inhibiting lysosomal biogenesis.

Conclusion: Our study demonstrates the utility of cancer organoids in drug discovery and identifies HHT as a promising therapeuticagent for ATC.

Ferroptosis, an iron-dependent form of regulated cell death characterized by overwhelming accumulation of lipid peroxidation, has emerged as a prominent area of interest in cancer research. Its underlying mechanisms are complex, and the high heterogeneity of hematologic malignancies adds additional challenges. Unlike solid cancers, hematologic malignancies lack fixed tissue architecture and exist within the dynamic bone marrow microenvironment, where iron metabolism, redox balance, and lipid remodeling are uniquely regulated. These differences create distinct metabolic vulnerabilities-particularly in iron and polyunsaturated fatty acid metabolism-that may render hematologic cancer cells more sensitive to ferroptotic stress. Given these unique features, a systematic understanding of ferroptosis in hematologic malignancies is critical for both elucidating disease mechanisms and exploring novel therapeutic strategies. This review summarizes the current understanding of ferroptosis in the pathogenesis and therapeutic resistance of hematologic malignancies, highlighting its mechanistic diversity across leukemia, lymphoma, and multiple myeloma. We also discuss emerging therapeutic strategies that exploit ferroptosis and outline key challenges and future directions for translating ferroptosis-based interventions into clinical practice.

Purpose: This study aimed to investigate the role of DNMT1 in CRC progression and its regulatory relationship with TRAF6 and EZH2.

Methods: DNMT1 expression was analyzed in CRC tissues and cell lines using public databases and experimental techniques, including Western blot and qRT-PCR. Functional assays, such as colony formation, transwell migration/invasion, and cell cycle analysis, were performed to assess the role of DNMT1 in CRC cell proliferation and metastasis. Mechanistic studies, including cycloheximide (CHX) chase assays, ubiquitination assays, and co-immunoprecipitation (Co-IP), were conducted to explore the regulation of DNMT1 stability and its effects on EZH2 protein stability. The regulatory axis was further validated using methylation-specific PCR (MSP), dual-luciferase assays, and immunohistochemistry (IHC) in CRC patient tissues.

Results: DNMT1 was significantly overexpressed in CRC tissues and cell lines, correlating with enhanced cell proliferation, migration, and invasion Mechanistically, DNMT1 is associated with CRC cell proliferation and regulate this process via upregulating cyclins D1/E2 and accelerating G1/S phase transition. Decitabine, a DNA methyltransferase inhibitor, induced DNMT1 degradation via the ubiquitin-proteasome pathway, with TRAF6 identified as a key E3 ubiquitin ligase mediating this process. TRAF6 was downregulated in CRC tissues and inversely correlated with DNMT1 expression. DNMT1 suppressed TRAF6 expression through promoter hypermethylation, forming a negative feedback loop. Additionally, DNMT1 stabilized EZH2 by inhibiting TRAF6-mediated ubiquitination, thereby enhancing EZH2-dependent oncogenic signaling. Functional experiments demonstrated that EZH2 was essential for DNMT1-mediated CRC progression.

Conclusion: This study reveals a novel Decitabine-TRAF6-DNMT1-TRAF6-EZH2 regulatory axis in CRC. Decitabine has dual effects, suggesting a new therapy.

Background: There is currently no unified consensus on the diagnosis and treatment of hepatoid adenocarcinoma of the stomach (HAS) and non-hepatoid AFP-producing gastric cancer (AFPGC). This study aims to explore the molecular similarities between the two, providing a basis for the diagnosis and precision treatment of these patients.

Methods: We retrospectively collected tumor tissues, adjacent tissues, and peripheral blood samples from 83 patients for whole-exome sequencing or transcriptome sequencing. Spearman correlation analysis, unsupervised clustering analysis and so on were performed to assess the similarity between different sample groups, explore the molecular features of non-hepatoid AFPGC and HAS, and compare their correlations.

Results: All the patient groups shared high-frequency mutated genes such as TP53, LRP1B, MUC16, CSMD3, and FAT4. Copy number variation analysis revealed similarities in the copy number variations between the two patient groups. The majority of patients in both groups exhibited amplification of the CCNE1 or ERBB2. PCA analysis based on transcriptomic data showed a clear clustering trend within the HAS and non-hepatoid AFPGC subgroups, which was distinct from conventional gastric adenocarcinoma. Moreover, unsupervised clustering analysis indicated that the samples within the different subgroups of the two groups had similar transcriptional expression patterns. Finally, we identified a potential therapeutic target, FAT4. Mutations in FAT4 further affect transcriptional expression and prognosis in gastric cancer patients, as well as influence immune infiltration and the response to immune checkpoint blockade therapy.

Conclusion: HAS and non-hepatoid AFPGC exhibit a high degree of similarity at both the genomic and transcriptomic levels.

Clinical trial number: Not applicable.

Background: Spinal ependymal tumors are a diverse group of neoplasms encompassing four subtypes: spinal ependymoma (SP-EPN), spinal ependymoma, MYCN-amplification (SP-EPN-MYCN), spinal myxopapillary ependymoma (SP-MPE), and spinal subependymoma (SP-SE). However, the molecular differences among these subtypes remain largely unknown.

Methods: Using an integrated multi-omics approach (whole-genome sequencing, RNA-seq, and mass spectrometry), we identified the distinct molecular characteristics of three subtypes except for SP-EPN-MYCN.

Results: In SP-EPN, abnormal enrichment of ciliary signaling, particularly involving the MKS complex, was evident. SP-MPE exhibited significant dysregulation of mitochondrial metabolism, reflecting a metabolic profile aligned with the Warburg effect. SP-SE tumors showed enhanced activity of immune-related pathways, including interferon signaling and extracellular vesicle dynamics, suggesting a distinct tumor microenvironment.

Conclusion: This pilot study identifies candidate molecular markers in a single-center spinal ependymal tumor cohort.

Clinical trial number: Not applicable.