Neoplasia最新文献

There is a continued need for identification of novel disease drivers of acute myeloid leukemia (AML) as many patients experience relapse and have poor clinical outcomes. Using genomic analyses of a study dataset of paired diagnosis and relapse specimens (n = 59), we identified recurrent downregulation of CCAAT-enhancer binding protein delta (CEBPD) expression at relapse and inferred CEBPD as one of the key regulators of gene transcription in a subset of relapse patients. Three independent public datasets validated downregulation of CEBPD expression at relapse and predicted it as a candidate tumor suppressor gene in AML. To evaluate CEBPD's tumor suppressor function, we performed complementary loss- and gain-of-function experiments in human AML cell lines OCI-AML2 and OCI-AML5. Consistent with the prediction, knockdown of CEBPD expression led to activation of MAPK signaling and upregulation of downstream effectors cyclin D1 and TNFα expression with concomitant increase in leukemic growth, while CEBPD overexpression resulted in induction of myeloid differentiation marker CD14 expression in the cell lines. Consistent with prior reports, our integrative genomic analyses and azacytidine treatment experiments further suggest a role for DNA methylation in downregulation of CEBPD expression during AML progression. Collectively, our results provide direct functional evidence for a tumor suppressor function of CEBPD in human cell lines and support prior studies implicating its epigenetic silencing in human AML.

Colorectal cancer (CRC) progression could be fueled by the activation of the unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress. The proline-rich Akt1 substrate of 40 kDa (PRAS40) is implicated in cancer progression, but its role in the UPR remains unclear. Herein, we demonstrate that PRAS40 promotes the inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) axis-dependent UPR in driving CRC progression. Mechanistically, PRAS40 interacts with ER chaperone glucose-regulated protein 78 (GRP78) and enhances its N-glycosylation. Moreover, PRAS40 improves the interaction between GRP78 and ST6 β-galactoside α-2, 6-sialyltransferase 1 (ST6Gal1), leading to increased α-2, 6-sialylation of GRP78 and the UPR triggered by ER stress. Furthermore, we identified the natural compound β-sitosterol as a novel ST6Gal1 inhibitor, which attenuated PRAS40-triggered tumor growth. Collectively, these findings unveil a PRAS40-ST6Gal1-GRP78 axis that drives CRC progression through activating the IRE1α-XBP-1-mediated UPR and nominate ST6Gal1 as a promising therapeutic target.

Background: Hepatocellular carcinoma (HCC) exhibits high recurrence rates and limited therapeutic options. Endothelial cell-specific molecule 1 (ESM1) and angiopoietin-like 4 (ANGPTL4) are implicated in tumor progression, yet their synergistic role in HCC lipid metabolism and angiogenesis remains unexplored.

Methods: We integrated multi-omics approaches, including RNA sequencing, metabolomics, and immunoprecipitation-mass spectrometry, in HCC cell lines and patient-derived xenograft models. Key experiments involved Co-IP, Western blotting, tube formation assays, and clinical tissue microarray analysis to validate the ESM1-ANGPTL4-FASN-trioleate axis.

Results: ESM1 and ANGPTL4 formed a positive feedback loop, stabilizing fatty acid synthase (FASN) to promote trioleate synthesis. Trioleate activated the NF-κB/IL-17 pathway in HCC cells and upregulated CD99 in endothelial cells, driving angiogenesis. In vivo, ESM1/ANGPTL4 knockdown suppressed tumor growth, which was rescued by trioleate supplementation. Clinical data revealed elevated ESM1/ANGPTL4 expression in bevacizumab-resistant HCC, correlating with poor prognosis.

Conclusions: The ESM1-ANGPTL4-FASN-trioleate axis orchestrates metabolic reprogramming and endothelial activation, representing a promising therapeutic target. Future studies should explore combination therapies targeting this axis and overcoming bevacizumab resistance in HCC.

TFE3-rearranged renal cell carcinoma (TFE3-RCC) is an aggressive kidney cancer driven by oncogenic TFE3 fusion transcription factors, yet the molecular machinery that enables these fusions to reprogram transcription and drive tumor growth remains poorly defined. Here, we identify the Cyclin C-CDK8/19 Mediator kinase module as an essential co-regulator of TFE3 fusion driven transcriptional programs and tumorigenesis. Inducible expression of PRCC-TFE3 in HK-2 cells, immortalized from normal renal epithelial cells, triggered a robust oncogene-induced senescence (OIS) phenotype. Using OIS as a functional readout, we performed a genome-wide CRISPR/Cas9 loss-of-function screen and identified CCNC, encoding Cyclin C, as an essential gene required for PRCC-TFE3 activity. Genetic disruption of CCNC or pharmacologic inhibition of CDK8/19 abrogated PRCC-TFE3 induced OIS, establishing the Mediator kinase module as a critical cofactor for PRCC-TFE3 dependent transcription. Mechanistically, PRCC-TFE3 promoted nuclear accumulation of Cyclin C and their co-occupancy at genomic regions bound and transcriptionally activated by PRCC-TFE3. RNA sequencing revealed that PRCC-TFE3 induced transcriptional programs, including lysosomal, TFEB-associated, and metabolic pathways, were broadly suppressed by CDK8/19 inhibition. Importantly, while PRCC-TFE3 and Cyclin C-CDK8/19 drive OIS in non-cancerous renal epithelial cells, this same transcriptional axis exerts a context dependent pro-tumorigenic function in TFE3-RCC. In xenografts established from patient derived TFE3-RCC cell lines, genetic deletion of CCNC suppressed tumor growth, whereas in an orthotopic syngeneic TFE3-RCC mouse model, pharmacologic CDK8/19 inhibition significantly reduced tumor progression. These findings define the Mediator kinase module as a mechanistic and therapeutic vulnerability in PRCC-TFE3 driven TFE3-RCC, providing a rationale for mechanism based targeted therapy.

Betel quid (BQ) chewing is a profound risk for oral squamous cell carcinoma (OSCC) in Southeast Asia. Yet, the detailed mechanisms by which BQ chewing damages the genome and creates a unique tumor niche that ultimately cause OSCC are still not fully understood. To address this, we conducted a multi-omics survey, including exome sequencing of tumor-normal pairs from 261 male patients with OSCC (129 habitual BQ chewers and 132 non-BQ users), alone with integrated single-cell and spatial transcriptomics of a set of tumors. Comparative analyses of the mutational catalog identified enrichment of significantly altered genes (e.g. mutations of TP53 and CHUK, copy gains of MAP3K13 and FADD, copy losses of CDKN2A) associated with BQ chewing. Assessment of oncogenic and co-occurring actionable alterations demonstrated frequently altered oncogenic pathways (Hippo and p53 signaling) and potential combination therapy opportunities linked to BQ use. In addition, evaluation of epithelial, immune, stromal expression programs in the corresponding tissue compartments revealed a shift of tumor microenvironment in BQ-related OSCC, characterized by induced hypoxia of tumor epithelium, altered immunosuppression of dendritic cells, and raised sprouting angiogenesis of tumor endothelium. Quantitative predictions of intercellular communications inferred a more heterogeneous cell-cell crosstalk among BQ-related OSCC, highlighted by extensive interactions of fibroblasts and dendritic cells with other non-epithelial cell types via mostly extracellular matrix-receptor signaling pathways. Collectively, these differences in genomic landscape and tumor niche suggest that OSCC caused by BQ chewing could be an etiological subtype different from their BQ-negative counterparts.

DFMO has been studied as a cancer therapeutic at doses ranging from 500 to 9,000 mg/m2/day. Lower doses are favored for cancer prevention studies while higher doses, often with chemotherapy, are studied in refractory cancers. DFMO inhibits the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase (ODC), an oncogene transcriptionally regulated by MYC. MYC genes are the principal oncogenic drivers of neuroblastoma, and ODC1 is co-amplified in a subset with dismal outcome, so DFMO is a rational therapeutic candidate. Low-dose DFMO has now been FDA-approved for high-risk patients though the mechanisms for its anti-tumor activity, and the exposures required to elicit them, remain obscure. We sought to define biomarkers of activity across exposures achieved in the clinic with low through high-dose DFMO. Polyamines support protein translation by providing spermidine, which is essential to hypusinate (and activate) the elongation factor, eIF5A. Selective binding of polyamines with tRNA and rRNA provide eIF5A-independent mechanisms of translation support. We show that low-dose DFMO does not extend survival in mouse models in vivo nor alter translation biomarkers in vitro. High-dose DFMO consistently extends survival in neuroblastoma models, and, in a subset of neuroblastoma cell lines, inhibits eIF5A hypusination and global translation at achievable concentrations. However, the concentration required to engage these changes across many cell lines exceeded that achievable even with high-dose DFMO. No correlation was seen among MYCN and/or ODC1 copy number and sensitivity to DFMO. Combining high-dose DFMO with additional agents to further deplete tumor polyamines may be necessary to fully engage polyamine-depletion effects on tumors, and more granular measures of translation, including codon-resolution ribosome profiling, may be required to define these effects.