Molecular Oncology

Oncogene-induced replication stress has been recognized as a major cause of genome instability in cancer cells. Increased expression of cyclin E1 caused by amplification of the CCNE1 gene is a common cause of replication stress in various cancers. Protein phosphatase magnesium-dependent 1 delta (PPM1D) is a negative regulator of p53 and has been implicated in termination of the cell cycle checkpoint. Amplification of the PPM1D gene or frameshift mutations in its final exon promote tumorigenesis. Here, we show that PPM1D activity further increases the replication stress caused by overexpression of cyclin E1...

The utility of multigene expression assays in advanced (≥4 positive lymph nodes) early breast cancer (EBC) is limited. We conducted exploratory transcriptomic analysis of 758 genes (Breast Cancer 360 panel, nCounter® platform; NanoString) in primary tumor samples collected during a phase 3 trial comparing adjuvant taxane-containing dose-dense chemotherapy (ddCTX) versus standard-dosed chemotherapy (stCTX) in resected EBC with ≥4 positive lymph nodes. Prognostic and predictive associations with disease-free survival (DFS) and overall survival (OS) were evaluated by Cox regression with false discovery rate (FDR) adjustment...

Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. The standard treatment achieves a median overall survival for GBM patients of only 15 months. Hence, novel therapies based on an increased understanding of the mechanistic underpinnings of GBM are desperately needed. In this study, we show that elevated expression of 28S rRNA (cytosine-C(5))-methyltransferase NSUN5, which methylates cytosine 3782 of 28S rRNA in GBM cells, is strongly associated with the poor survival of GBM patients...

Previous studies have uncovered the key role of circular RNAs (circRNAs) in various diseases, including cancer. However, the growth-inhibitory effects of circRNAs on esophageal squamous cell carcinoma (ESCC) have not been completely elucidated. This study characterized a newly identified circRNA derived from exons 9-13 of TNRC6B (named circ-TNRC6B). The expression of circ-TNRC6B in ESCC tissues was markedly downregulated when compared with that in non-tumor tissues. In 53 ESCC cases, circ-TNRC6B expression was negatively correlated with the T stage...

In previous studies, we demonstrated that panobinostat, a histone deacetylase inhibitor, and the proteasomal inhibitor bortezomib displayed synergistic therapeutic activity against pediatric and adult high-grade gliomas. Despite the remarkable initial response to this combination, resistance emerged. Here, in this study, we aimed to investigate the molecular mechanisms underlying the anticancer effects of panobinostat and marizomib, a brain-penetrant proteasomal inhibitor, and the potential for exploitable vulnerabilities associated with acquired resistance...

CUB domain-containing protein 1 (CDCP1) contributes to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance by regulating EGFR signaling pathways and is a potential target in lung cancer treatment. This study aims to identify a CDCP1 reducer that synergistically improves TKI treatment. Utilizing a high-throughput drug screening system, a phytoestrogen 8-isopentenylnaringenin (8PN) was identified. Upon 8PN treatment, CDCP1 protein levels and malignant features were reduced. 8PN exposure caused the accumulation of lung cancer cells in G0/G1 phase and increased the proportion of senescent cells...

The presence of large genomic rearrangements (LGRs) has been heavily investigated in breast and ovarian cancer. However, correlations between LGRs and cancer types beyond these two have not been extensively profiled, likely due to the highly inefficient methods of detecting these types of alterations. This study utilized next-generation sequencing (NGS) to analyze and classify the germline LGR profile in 17,025 cancer patients across 22 cancer types. We characterized newly identified LGRs based on predicted pathogenicity and took a closer look at genes that acquire both germline and somatic mutations within our samples...

Local hypoxia occurs in most solid tumors and is associated with aggressive disease and therapy resistance. Widespread changes in gene expression play a critical role in the biological response to hypoxia. However, most research has focused on hypoxia-inducible genes as opposed to those which are decreased in hypoxia. We demonstrate that chromatin accessibility is decreased in hypoxia, predominantly at gene promoters and specific pathways are impacted including DNA repair, splicing and the R-loop interactome...

Synthetic biology has made it possible to rewire natural cellular responses to treat disease, notably demonstrated by chimeric antigen receptor (CAR) T cells as cancer immunotherapy. Building on the success of T-cell activation using synthetic receptors, the field is now investigating how induction of noncanonical signalling pathways and sophisticated synthetic gene circuitry can enhance the antitumour phenotype of engineered T cells. This commentary explores two recently published studies that provide proof of concept for how new technologies achieve this...

Downregulation of the DNA repair protein WD40-encoding RNA antisense to p53 (WRAP53) has been associated with radiotherapy resistance and reduced cancer survival. The aim of this study was to evaluate WRAP53 protein and RNA levels as prognostic and predictive markers in the SweBCG91RT trial, in which breast cancer patients were randomized for postoperative radiotherapy. Using tissue microarray and microarray-based gene expression, 965 and 759 tumors were assessed for WRAP53 protein and RNA levels, respectively...

The AMP-activated protein kinase (AMPK)-related kinase NUAK1 (NUAK family SNF1-like kinase 1) has emerged as a potential vulnerability in MYC-dependent cancer but the biological roles of NUAK1 in different settings are poorly characterised and the spectrum of cancer types that exhibit a requirement for NUAK1 is unknown. Unlike canonical oncogenes, NUAK1 is rarely mutated in cancer and appears to function as an obligate facilitator rather than a cancer driver per se. Although numerous groups have developed small-molecule NUAK inhibitors, the circumstances that would trigger their use and the unwanted toxicities that may arise as a consequence of on-target activity are thus undetermined...

Currently, the knowledge of long non-coding RNA (lncRNA)-encoded peptides is quite lacking in esophageal squamous cell carcinoma (ESCC). In this study, we simultaneously identified six lncRNA open reading frames (ORFs) with peptide-coding abilities including lysine-specific demethylase 4A antisense RNA 1 (KDM4A-AS1) ORF by combining weighted gene co-expression network analysis (WGCNA) for ESCC clinical samples, ribosome footprints, ORF prediction, mass spectrometry (MS) identification, and western blotting...

European cancer research stakeholders met in October 2022 in Heidelberg, Germany, at the 5th Gago conference on European Cancer Policy, to discuss the current cancer research and cancer care policy landscape in Europe. Meeting participants highlighted gaps in the existing European programmes focusing on cancer research, including Europe's Beating Cancer Plan (ECBP), the Mission on Cancer (MoC), Understanding Cancer (UNCAN.eu), and the joint action CRANE, and put forward the next priorities, in the form of the Heidelberg Manifesto for cancer research...

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Extracellular vesicles (EVs) are an important regulatory factor for natural killer cell activity (NKA) in the tumor microenvironment. The relationship between circulating EVs in the peripheral blood and natural killer (NK) cells in prostate cancer is unclear. This study aims to investigate the key regulators in the interaction between circulating EVs and NK cells in prostate cancer patients before and after tumor removal. NK-cell characteristics were prospectively assessed in 79 patients treated with robot-assisted laparoscopic radical prostatectomy (RARP) preoperatively and postoperatively...

LIM protein-domain containing protein Ajuba (encoded by AJUBA) functions as a scaffold protein to regulate protein-protein interactions, signaling transduction and genes transcription. AJUBA expression is higher in colorectal cancer (CRC) tissues compared with normal tissues, but its specific molecular function in CRC progression is still not very clear. Here, we found that, in CRC cancer cell lines, overexpression of AJUBA decreased p53 levels, whereas knockdown of AJUBA significantly increased p53 levels...

Accuracy and transparency of scientific data are becoming more and more relevant with the increasing concern regarding the evaluation of data reproducibility in many research areas. This concern is also true for quantifying coding and non-coding RNAs, with the remarkable increase in publications reporting RNA profiling and sequencing studies. To address the problem, we propose the following recommendations: 1) accurate documentation of experimental procedures in Materials and Methods (and not only in the supplementary information, as many journals have a strict mandate for making Materials and Methods as visible as possible in the main text); 2) submission of RT-qPCR raw data for all experiments reported; and 3) adoption of a unified, simple format for submitted RT-qPCR raw data...

Human epidermal growth factor receptor 2 (ErbB2/HER2) is a tyrosine kinase receptor that is overexpressed in 25% of primary human breast cancers, as well as in multiple other cancers. HER2-targeted therapies improved progression-free and overall survival in patients with HER2+ breast cancers. However, associated resistance mechanisms and toxicity highlight the need for new therapeutic approaches for these cancers. We recently established that, in normal cells, HER2 is stabilized in a catalytically repressed state by a direct interaction with members of the ezrin/radixin/moesin (ERM) family...

Hepatocellular carcinoma (HCC) is the third deadliest and sixth most common cancer in the world. Histone-lysine N-methyltransferase EHMT2 (also known as G9a) is a histone methyltransferase frequently overexpressed in many cancer types, including HCC. We showed that Myc-driven liver tumors have a unique H3K9 methylation pattern with corresponding G9a overexpression. This phenomenon of increased G9a was further observed in our c-Myc-positive HCC patient-derived xenografts. More importantly, we showed that HCC patients with higher c-Myc and G9a expression levels portend a poorer survival with lower mean survival months...

Treatment with immune checkpoint inhibitors (ICI) has revolutionized cancer management for multiple tumor types, including breast cancer. However, not all patients respond to ICI and unraveling the determinants and mechanisms of response still remains an unmet need. A recent study has uncovered the critical role of eosinophils in mediating immunotherapy effect in breast cancer, mainly by stimulating the activation of CD8+ T-cells. Furthermore, the intratumoral eosinophil recruitment was directed by CD4+ T-cells and the interleukins IL-5 and IL-33, thus providing the rationale for targeting eosinophils to enhance ICI response...