Molecular Oncology最新文献

While the incidence of endometrial cancer is increasing among all US women, Black women face higher mortality rates. The reasons for this remain unclear. In this study, whole genome differential methylation analysis, along with state-of-the-art computational methods such as the recursive feature elimination technique and supervised/unsupervised machine learning models, was used to identify 38 epigenetic signature genes (ESGs) and four core-ESGs (cg19933311: TRPC5; cg09651654: APOBEC1; cg27299712: PLEKHG5; cg03150409: WHSC1) in endometrial tumors from Black and White women, incorporating genetic ancestry estimation. Methylation at two Core-ESGs, namely APOBEC1 and PLEKHG5, showed statistically significant overall survival differences between the two ancestral groups (Likelihood ratio test; P value = 0.006). Moreover, our comprehensive ancestry-based analysis revealed that tumors from women with high African ancestry exhibited increased hypomethylation compared to those with low African ancestry. These hypomethylated genes were enriched in drug metabolism pathways, indicating a potential link between genetic ancestry, epigenetic modifications, and pharmacogenomic responses. Combining ancestry, race, and disease type may help identify which patient groups will benefit most from these biomarkers for targeted treatments.

Super-enhancer-associated transcription factor networks define cell identity in neuroblastoma (NB). Dysregulation of these transcription factors contributes to the initiation and maintenance of NB by enforcing early developmental identity states. We report that the class I basic helix-loop-helix (bHLH) transcription factor 4 (TCF4; also known as E2-2) is a critical NB dependency gene that significantly contributes to these identity states through heterodimerization with cell-identity-specific bHLH transcription factors. Knockdown of TCF4 significantly induces apoptosis in vitro and inhibits tumorigenicity in vivo. We used genome-wide expression profiling, TCF4 chromatin immunoprecipitation sequencing (ChIP-seq) and TCF4 immunoprecipitation-mass spectrometry to determine the role of TCF4 in NB cells. Our results, along with recent findings in NB for the transcription factors T-box transcription factor TBX2, heart- and neural crest derivatives-expressed protein 2 (HAND2) and twist-related protein 1 (TWIST1), propose a role for TCF4 in regulating forkhead box protein M1 (FOXM1)/transcription factor E2F-driven gene regulatory networks that control cell cycle progression in cooperation with N-myc proto-oncogene protein (MYCN), TBX2, and the TCF4 dimerization partners HAND2 and TWIST1. Collectively, we showed that TCF4 promotes cell proliferation through direct transcriptional regulation of the c-MYC/MYCN oncogenic program that drives high-risk NB. Mechanistically, our data suggest the novel finding that TCF4 acts to support MYC activity by recruiting multiple factors known to regulate MYC function to sites of colocalization between critical NB transcription factors, TCF4 and MYC oncoproteins. Many of the TCF4-recruited factors are druggable, giving insight into potential therapies for high-risk NB. This study identifies a new function for class I bHLH transcription factors (e.g., TCF3, TCF4, and TCF12) that are important in cancer and development.

Glioblastoma (GB), the most common and aggressive brain tumor, demonstrates intrinsic resistance to current therapies, resulting in poor clinical outcomes. Cancer progression can be partially attributed to the deregulation of protein translation mechanisms that drive cancer cell growth. In this study, we present the translatome landscape of GB as a valuable data resource. Eight patient-derived GB sphere cultures (GSCs) were analyzed using ribosome profiling and messenger RNA (mRNA) sequencing. We investigated inter-cell-line differences through differential expression analysis at both the translatome and transcriptome levels. Translational changes post-radiotherapy were assessed at 30 and 60 min. The translation of non-coding RNAs (ncRNAs) was validated using in-house and public mass spectrometry (MS) data, whereas RNA expression was confirmed by quantitative PCR (qPCR). Our findings demonstrate that ribosome sequencing provides more detailed information than MS or transcriptional analyses. Transcriptional similarities among GSCs correlate with translational similarities, aligning with previously defined subtypes such as proneural and mesenchymal. Additionally, we identified a broad spectrum of open reading frame types in both coding and non-coding mRNA regions, including long non-coding RNAs (lncRNAs) and pseudogenes undergoing active translation. Translation of ncRNAs into peptides was independently confirmed by in-house data and external MS data. We also observed that translational regulation of histones (downregulated) and splicing factors (upregulated) occurs in response to radiotherapy. These data offer new insights into genome-wide protein synthesis, identifying translationally regulated genes and alternative translation initiation sites in GB under normal and radiotherapeutic conditions, providing a rich resource for GB research. Further functional validation of differentially expressed genes after radiotherapy is needed. Understanding translational control in GB can reveal mechanistic insights and identify currently unknown biomarkers, ultimately enhancing the diagnosis and treatment of this aggressive brain cancer.

The transcriptomic classification of primary colorectal cancer (CRC) into distinct consensus molecular subtypes (CMSs) is a well-described strategy for patient stratification. However, the molecular nature of CRC metastases remains poorly investigated. To this end, this study aimed to identify and compare organotropic CMS frequencies in CRC liver and brain metastases. Compared to reported CMS frequencies in primary CRC, liver metastases from CRC patients were CMS4-enriched and CMS3-depleted, whereas brain metastases mainly clustered as CMS3 and rarely as CMS4. Regarding overall survival rates, CMS4 was the most favorable subtype for patients with hepatic lesions, followed by CMS1 and CMS2. The survival of patients with brain metastases did not correlate with CMS. However, we identified a CMS3-related metabolic gene signature, specifically upregulated in central nervous system (CNS)-infiltrating CRC, as a negative prognostic marker and potential tumor progressor. In summary, subtyping of CRC metastases revealed an organotropic CMS distribution in liver and brain with impact on patient survival. CNS-infiltrating CRC samples were enriched for CMS3 and predictive metabolic biomarkers, suggesting metabolic dysregulation of CRC cells as a prerequisite for metastatic colonization of the brain.

Cytokines have gained attention in oncology in recent years, especially in the context of immunotherapy. Although immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, there are still some challenges to be faced, such as the lack of predictive biomarkers as well as the emergence of resistance and their severe side effects. In this Viewpoint, we discuss the potential of cytokines, the soluble mediators of cancer-associated inflammation, in immunotherapy. Indeed, both the activation and inhibition of cytokines have been suggested as potential strategies to overcome immunotherapy resistance. In addition, serum levels of certain cytokines can predict response to immunotherapy, and cytokine inhibition could also contribute to prevent side effects induced by ICIs. Thus, although further research is still required, data support that cytokine-based therapies could be an attractive therapeutic strategy for cancer patients treated with immunotherapy in the near future.

Glioblastoma is the most common form of primary malignant brain tumor in adults and one of the most lethal human cancers, with high recurrence and therapy resistance. Glioblastoma cells display extensive genetic and cellular heterogeneity, which precludes a unique and common therapeutic approach. The standard of care in glioblastoma patients includes surgery followed by radiotherapy plus concomitant temozolomide. As in many other cancers, cell signaling is deeply affected due to mutations or alterations in the so-called molecular drivers. Moreover, glioblastoma cells undergo metabolic adaptations to meet the new demands in terms of energy and building blocks, with an increasing amount of evidence connecting metabolic transformation and cell signaling deregulation in this type of aggressive brain tumor. In this review, we summarize some of the most common alterations both in cell signaling and metabolism in glioblastoma, presenting an integrative discussion about how they contribute to therapy resistance. Furthermore, this review aims at providing a comprehensive overview of the state-of-the-art of therapeutic approaches and clinical trials exploiting signaling and metabolism in glioblastoma.

There are two key signatures of pediatric cancers: (a) higher prevalence of germline alterations and (b) heterogeneity in alteration types. Recent population-based assessments have demonstrated that children with birth defects (BDs) are more likely to develop cancer even without chromosomal anomalies; therefore, explorations of genetic alterations in children with BDs and cancers could provide new insights into the underlying mechanisms for pediatric tumor development. We performed whole-genome sequencing (WGS) on blood-derived DNA for 1556 individuals without chromosomal anomalies, including 454 BD probands with at least one type of malignant tumor, 757 cancer-free children with BDs, and 345 healthy individuals, focusing on copy number variation (CNV) analysis. Roughly half of the children with BD-cancer have CNVs that are not identified in BD-only/healthy individuals, and CNVs are not evenly distributed among these patients. Strong heterogeneity was observed, with a limited number of cancer predisposition genes containing CNVs in more than three patients. Moreover, functional enrichments of genes with CNVs showed that dozens of patients have variations related to the same biological pathways, such as deletions of genes with neurological functions and duplications of immune response genes. Phenotype clustering uncovered recurrences of patients with sarcoma: A notable enrichment was observed involving non-coding RNA regulators, showing strong signals related to growth and cancer regulations in functional analysis. In conclusion, we conducted one of the first genomic studies exploring the impact of CNVs on cancer development in children with BDs, unveiling new insights into the underlying biological processes.

Glioblastoma cells rely on connexin 43 (Cx43)-based gap junctions (GJs) for intercellular communication, enabling them to integrate into a widely branched malignant network. Although there are promising prospects for new targeted therapies, the lack of clinically feasible GJ inhibitors has impeded their adoption in clinical practice. In the present study, we investigated tonabersat (TO), a blood-brain-barrier-penetrating drug with GJ-inhibitory properties, in regard to its potential to disassemble intercellular connectivity in glioblastoma networks. Fluorescence-guided measurements of calcein cell-to-cell transfer were used to study functional intercellular connectivity. Specific DNA fragmentation rates of propidium iodide-stained nuclei were measured as a surrogate readout for cell death using flow cytometry. CRISPR/Cas9-mediated gene editing of Cx43 served as a validation tool of cellular effects related to Cx43 GJ inhibition. 3' mRNA sequencing was performed for molecular downstream analysis. We found that TO reduced intercellular GJ-mediated cytosolic traffic and yielded a significant reduction of tumor microtube (TM) length. TO-mediated inhibition of cellular tumor networks was accompanied by a synergistic effect for temozolomide-induced cell death. CRISPR/Cas9 Cx43-knockout revealed similar results, indicating that TO-mediated inhibitory effects rely on the inhibition of Cx43-based GJs. Gene set enrichment analyses found that GJ-mediated synergistic cytotoxic effects were linked to a significant upregulation of cell death signaling pathways. In conclusion, TO disrupts TM-based network connectivity via GJ inhibition and renders glioblastoma cells more susceptible to cytotoxic therapy. Given its previous use in clinical trials for migraine therapy, TO might harbor the potential of bridging the idea of a GJ-targeted therapeutic approach from bench to bedside.

Transposable elements provide material for novel gene formation. In particular, DNA transposons have contributed several essential genes involved in various physiological or pathological conditions. Here, we discuss recent findings by Tu et al. in Molecular Cell that identify Pogo transposon-derived gene POGK as tumor suppressor in triple-negative breast cancer (TNBC) by regulating ribosome biogenesis and restricting cell growth. An isoform-switch in TNBC results in the loss of POGK capacity to recruit the epigenetic corepressor TRIM28 and to exert its repressive functions. These findings shed light on the potential for TE-derived genes in providing new therapeutic opportunities for highly malignant TNBC.