Jul 2026· Asian Pacific Journal of Cancer Biology· 0 citations· 31 references
TL;DR
The study suggests that the inhibition of the Wnt/LEF1 axis is associated with the potential activation of a compensatory survival mechanism, involving the NF-kappa B/AP-1 pathway.
Abstract
Background: Chronic lymphocytic leukemia (CLL) remains a major clinical challenge, mainly due to the persistent drug resistance of leukemia- affected cells targeted therapies. The transcription factor gene LEF1, and its governing Wnt/β-catenin axis, is is a well-established driver as a fundamental driver promoting cellular growth and proliferation in this malignancy consequently that we designed this current study to identify the precise compensatory survival mechanism employed by CLL cells following successful disruption of LEF1 signaling.
Methods: Gene expression data were obtained from the GEO database (GSE299964) to study and analyzed LEF1inhibition in CLL cell. Differential expression analysis (DEA) and pathway enrichment analysis were used to identify inhibited and activated pathways also was designed a protein-protein interaction network (PPI) to identify and visualize the interaction. Statistical analyses were performed within the R environment (version 4.4.1).
Results: By used DEA, the results showed significant inhibition of the Wnt axis (LEF1, Log2FC: -6.22) and concurrent activation of the NF-κB/AP-1 pathway, particularly SLC3A2 (+3.59) and JUN (+3.10). And downregulation in key growth factors was observed specifically CCND1 and MYC. In contrast, the pathway enrichment analysis suggested strong statistical of the NF-kappa B, and an increase in the transcription factors was observed NFKB1 and JUN. It is important that the visualization of the PPI network provided visual evidence the existence of direct regulatory links connecting suppressed Wnt genes to activated NF-kappa B genes, this suggesting a potential emerging therapeutic dependency.
Conclusion: The study suggests that the inhibition of the Wnt/LEF1 axis is associated with the potential activation of a compensatory survival mechanism, involving the NF-kappa B/AP-1 pathway. These results indicate that chronic lymphocytic leukemia cells this reciprocal interaction may be used as an adaptive immune response to the disruption of the primary pathway. This aggregation strategy may represent a promising way to address anticipated resistance mechanisms, although further functional and laboratory studies are needed to validate them.
Acute myeloid leukemia (AML) represents a type of malignant hematological disease that is usually caused by the dysregulated developmental program of leukemia stem cells (LSCs). Here, we report that an unappreciated RNA-binding protein, Rbm5, selectively promotes murine leukemogenesis, maintains LSC self-renewal in vivo, and is dispensable for normal hematopoiesis. Rbm5 is highly expressed in LSCs, and its deficiency results in specifically defective LSC function, along with inhibition of self-renewal gene expression and induction of myeloid differentiation. Multi-disciplinary mechanistic investigations further identified Myc as the major and direct transcriptional target of Rbm5 in primary leukemia cells. Moreover, RBM5 not only interacts with MYC but also maintains its protein levels, thereby sustaining the Myc downstream transcriptional network through its proper genome-wide occupancy. Forced expression of Myc sufficiently rescued the Rbm5-depleted LSC defects. Thus, our study demonstrates that Rbm5 regulates the AML LSC program through non-canonical transcriptional mechanisms, providing a strong rationale for targeting Rbm5 therapeutically. In Brief. Zhang et al. illustrate the role of Rbm5 in sustaining the self-renewal program in leukemia stem. cells (LSCs) primarily through the Myc transcriptional network. Specifically, Rbm5 loss results in a significant decrease in Myc protein levels, thereby disrupting. the Myc downstream transcriptional network in LSCs. Notably, this effect is specific to LSCs, as. normal hematopoietic stem cells (HSCs) do not exhibit such changes upon Rbm5 loss.
BACKGROUND
Gliomas are highly malignant brain tumors characterized by an immunosuppressive microenvironment, which limits therapeutic efficacy and contributes to poor clinical outcomes. The WNT/β-catenin signaling pathway is critically involved in tumor progression, and FZD5, a key receptor within this pathway, may participate in immune regulation. However, its specific role and underlying mechanisms in glioma remain unclear.
METHODS
RNA-seq and microarray datasets from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA), together with single-cell RNA sequencing (scRNA-seq) datasets from GEO, were comprehensively analyzed. The Seurat package was used to identify macrophage-related clusters and mitophagy-associated pathways. Cox and LASSO regression analyses, along with a prognostic nomogram, were applied to evaluate the prognostic significance of FZD5. Immune infiltration, functional enrichment, and immunotherapy response analyses were conducted, followed by validation using spatial transcriptomics, immunohistochemistry, and in vitro assays.
RESULTS
In bulk glioma transcriptomes, FZD5 emerged as an independent predictor of poor prognosis. Crucially, single-cell and spatial analyses revealed that the biologically significant FZD5 signal originated predominantly within tumor-associated macrophages (TAMs), where it colocalized with the M2 marker CD163. Consistently, elevated FZD5 levels correlated with increased myeloid infiltration and an immunosuppressive tumor microenvironment. Functionally, macrophage-expressed FZD5 was associated with mitophagy-related programs and promoted an M2-skewed phenotype, thereby enhancing glioma cell proliferation, migration, and invasion via macrophage-glioma crosstalk.
CONCLUSION
FZD5 is a TAM-enriched marker in glioma tissues and a potential regulator of macrophage-associated immunosuppressive programs, supporting its utility as a prognostic biomarker and a candidate target for microenvironment-oriented interventions in glioma.
Background Gastric cancer (GC) constitutes a substantial global public health challenge, and the lack of tractable molecular targets limits therapeutic progress. Mesoderm-Specific Transcript (MEST) has been implicated in tumor-related signaling, yet its functional role and druggability in GC remain undefined. Methods The analyses of GC tissue microarrays and cohorts were performed to evaluate MEST expression and its clinical significance. CRISPR/Cas9-mediated MEST knockout was used to characterize its oncogenic functions in GC cells and xenograft models. Integrated RNA sequencing and pathway analysis was utilized to elucidate signaling pathways under the regulation of MEST. A structure-guided virtual screen combined with SPR binding and phenotypic assays were employed to discover small molecules targeting MEST. The therapeutic effects and mechanism of the lead compound were evaluated using GC cell lines, patient-derived organoids, cell-derived xenograft (CDX), and patient-derived xenograft (PDX) models. Methods MEST expression in GC tissues was elevated and linked to poor prognosis. Functionally, genetic ablation of MEST impaired GC cell proliferation, invasion, migration, and suppressed tumor growth in CDX models. Screening of approved-compound libraries identified cobicistat as a previously unrecognized high-affinity candidate MEST-inhibitory compound. Cobicistat suppressed tumor growth across a panel of preclinical GC models, including cell lines, organoids, CDX and PDX. Mechanistically, MEST may drive GC progression by activating the NF-κB pathway, whereas cobicistat may antagonize MEST binding and blocked NF-κB pathway. Conclusion MEST functions as a key oncoprotein driving GC progression via NF-κB activation. Cobicistat, a candidate MEST-inhibitory compound, exhibits favorable preclinical efficacy and safety, providing a promising candidate for targeted GC therapy.
Hongtai Cao, Huili Ye, Wentao Zhang et al.· Frontiers in Oncology· 0 citations
Pediatric cancers are frequently driven by genomic alterations that result in aberrant transcription factor activity and impaired differentiation during tissue development. Normal development requires precise patterns of gene expression programs, which are regulated by epigenetic-modifying complexes. Epigenetic regulation of transcription is critical for maintaining a de-differentiated oncogenic state in cancers, particularly pediatric, and targeting disease-relevant epigenetic regulators can exhibit antitumor activity.
To identify protein complex-level dependencies required for neuroblastoma, a pediatric cancer of the developing peripheral nervous system, we curated a list of protein complexes using the CORUM database and mined the Dependency Map (DepMap) using single sample gene set enrichment analysis. This analysis identified the non-canonical PRC1.1 complex, which represses transcriptional activity through ubiquitination of histone 2A, lysine 119 (H2AK119Ub), is a selectively enriched dependency in neuroblastoma. Knockout of several PRC1.1 subunits (i.e. PCGF1, BCOR, and KDM2B) reduced neuroblastoma growth, arrested the cell cycle, and induced a neuronal differentiation program. While no known direct inhibitors of non-canonical PRC1.1 exist, co-dependency analysis of PRC1.1 subunits against all other genes in DepMap identified that the deubiquitinase USP7 strongly correlated with PRC1.1 dependency. Treatment with XL177A, a small molecule inhibitor of USP7, significantly reduced neuroblastoma growth in both cellular and animal models. Integrated RNA- and ChIP-sequencing showed that both PRC1.1 knockout and USP7 inhibition resulted in highly correlated transcriptional alterations and reduced H2AK119Ub deposition on chromatin, suggesting that USP7 inhibition reduced neuroblastoma growth through a PRC1.1-dependent mechanism. Mechanistically, global proteomics and ubiquitinomics revealed that USP7 inhibition disrupted non-canonical PRC1 complex assembly, resulting in destabilization of PRC1.1 and subsequent proteolysis.
Our findings expand our understanding of the chromatin complexes required to maintain a de-differentiated state in neuroblastoma and suggest the therapeutic potential for USP7 inhibitors in the treatment of neuroblastoma.
Nathaniel W. Mabe. Therapeutic targeting of PRC1 complexes to induce neuroblastoma differentiation [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B010.
Nathaniel W. Mabe· Clinical Cancer Research· 0 citations
Genome-wide CRISPR screens have systematically identified genes required for cancer cell survival, yet these studies are typically performed under standardized conditions that do not fully recapitulate the physiological stresses encountered within the tumor microenvironment. In a recent issue of Nature Genetics, Cheruiyot and colleagues perform genome-wide loss-of-function screens under inflammatory conditions induced by interferon-β (IFN-β), interferon-γ (IFN-γ), and tumor necrosis factor (TNF), revealing that distinct cytokines impose different genetic requirements for tumor cell survival. The study shows that inflammatory signaling reshapes genetic dependency landscape in a cytokine-specific manner. Mechanistic analyses identify the glycosylphosphatidylinositol (GPI) transamidase complex and FITM2 as representative examples of genes that become selectively required under inflammatory stress by maintaining membrane protein maturation, endoplasmic reticulum homeostasis, and resistance to oxidative stress. These findings broaden our understanding of how inflammatory cytokines influence tumor cell biology beyond transcriptional regulation and immune recognition. More broadly, the study highlights the value of incorporating physiologically relevant conditions into functional genetic screens, suggesting that conventional dependency maps capture only part of the genetic requirements for tumor survival. Applying similar approaches to other microenvironmental stresses-including hypoxia, metabolic competition, extracellular matrix remodeling, and stromal signaling-may uncover additional therapeutic opportunities for cancer immunotherapy.
Zihan Ning, Guangchuan Wang· Cancer Research· 0 citations
Background Most types of programmed cell death (PCD) have been demonstrated to play critical roles in the pathogenesis and prognosis of lung squamous cell carcinoma (LUSC). However, the specific type of PCD with the most prominent driving effect and regulatory value in LUSC remains unclear. Methods Multi-omics data were integrated, and a multimodal autoencoder was employed to identify prognosis-related PCD gene modules and conduct weight ranking, leading to the construction of a PCD-associated neural network prognostic model. Summary-data-based Mendelian Randomization (SMR) analysis was applied to validate the causal relationship between key genes and LUSC. Combined with single-cell and spatial transcriptomics analyses, tumor–immune cell interactions were characterized, and the regulatory mechanism by which tumor cells modulate PCD in key immune cells through specific pathways was verified via cellular experiments. Results Twelve prognosis-related PCD gene modules were identified in LUSC, among which the Pyroptosis_4 module emerged as the core risk signature. The prognostic model based on Pyroptosis_4 enabled effective risk stratification of early-stage patients. SMR analysis confirmed that the key pyroptosis gene NOD1 was directly associated with LUSC susceptibility, and NOD1 expression in M2 macrophages regulated the tumor immune microenvironment. Tumor cells formed a close spatial network with NOD1- M2 macrophages and inhibited pyroptosis in M2 macrophages through the MDK/NCL signaling pathway. Conclusion Pyroptosis plays a crucial role in the prognosis of LUSC, and this effect is associated with differential NOD1 expression in M2 macrophages. Tumor cells and NOD1- M2 macrophages establish spatial interactions via the MDK/NCL pathway, emphasizing a potential candidate target for tumor immunoregulation-based strategies.
Taihao Wang, Wei Zhang, Zhihao He et al.· Frontiers in Cell and Develo...· 0 citations