Exploring high-throughput drug sensitivity testing in neuroblastoma cell lines and patient-derived tumor organoids in the era of precision medicine.

Introduction: Despite druggable events to be present in 80 % of neuroblastomapatients within the Princess Máxima Center precision medicine program 'iTHER', clinical uptake of treatment recommendations has been low, and the clinical impact for individual patients remains hard to predict. This stresses the need for a method integrating genomics and transcriptomics with functional approaches into therapeutic decision making.

Methods: We aimed to launch an online repository integrating genomics and transcriptomics with high-throughput drug screening (HTS) of nineteen commonly used neuroblastoma cell lines and fifteen neuroblastoma patient-derived organoids (NBL-PDOs).

KRAS mutation status integrated with RNA subtyping improves prognostic modeling in FOLFIRINOX-treated metastatic pancreatic cancer.

Background: First-line chemotherapy (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin [FOLFIRINOX]) benefits few patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Prognostic markers for treatment-related survival are needed. This study validated the added benefit of whole-genome sequencing (WGS) to transcriptome-based classification in modeling FOLFIRINOX-related survival.

Biglycan-driven risk stratification in ZFTA-RELA fusion supratentorial ependymomas through transcriptome profiling.

Recent genomic studies have allowed the subdivision of intracranial ependymomas into molecularly distinct groups with highly specific clinical features and outcomes. The majority of supratentorial ependymomas (ST-EPN) harbor ZFTA-RELA fusions which were designated, in general, as an intermediate risk tumor variant. However, molecular prognosticators within ST-EPN ZFTA-RELA have not been determined yet.

Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability.

Colorectal cancer (CRC) is stratified into four consensus molecular subtypes (CMS1-4). CMS3 represents the metabolic subtype, but its wiring remains largely undefined. To identify the underlying tumorigenesis of CMS3, organoids derived from 16 genetically engineered mouse models are analyzed.

Tumor gene expression is associated with venous thromboembolism in patients with ductal pancreatic adenocarcinoma.

Introduction: In patients with pancreatic cancer, the risk of venous thromboembolism (VTE) is high compared to other cancer types, suggesting that tumor-intrinsic features drive hypercoagulability. Tumor gene expression analysis may help unravel the pathogenesis of VTE in these patients and help to identify high-risk patients.

Aim: To evaluate the association between tumor gene expression patterns and VTE in patients with pancreatic cancer.

NanoCMSer: a consensus molecular subtype stratification tool for fresh-frozen and paraffin-embedded colorectal cancer samples.

Colorectal cancer (CRC) is a significant contributor to cancer-related mortality, emphasizing the need for advanced biomarkers to guide treatment. As part of an international consortium, we previously categorized CRCs into four consensus molecular subtypes (CMS1-CMS4), showing promise for outcome prediction. To facilitate clinical integration of CMS classification in settings where formalin-fixed paraffin-embedded (FFPE) samples are routinely used, we developed NanoCMSer, a NanoString-based CMS classifier using 55 genes.

Reporting Bone Cytopathology-A Proposal Based on a Single Tertiary Centre Experience.

Objective: Fine-needle aspiration cytology (FNAC) from bone lesions has been proven to be a useful diagnostic tool but lacks standardisation. The aim of the study was to evaluate the diagnostic utility of FNAC as a basis to propose and test a reporting system for bone reporting cytopathology.

Methods: This retrospective study is based on patients with bone lesions, that were approached by cytology at Skåne University Hospital, Sweden between 2015 and 2023.

Identification of pancreatic cancer-specific protease substrates for protease-dependent targeted delivery.

Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges due to the inadequacy of existing chemotherapeutics, which often result in toxicity-dependent dose limitations and premature cessation of therapy. Targeted delivery of therapeutic molecules offers a promising solution. Given that PDAC is marked by a desmoplastic reaction with extensive aberrant protease activity, protease-dependent targeted delivery could minimize off-target toxicities and is of increasing interest.

Identifying colorectal cancer-specific vulnerabilities in the Wnt-driven long non-coding transcriptome.

Background: Aberrant Wnt pathway activation is a key driver of colorectal cancer (CRC) and is essential to sustain tumour growth and progression. Although the downstream protein-coding target genes of the Wnt cascade are well known, the long non-coding transcriptome has not yet been fully resolved.

Objective: In this study, we aim to comprehensively reveal the Wnt-regulated long non-coding transcriptome and exploit essential molecules as novel therapeutic targets.

Hypoxia Abrogates Tumor-Suppressive Activities of C/EBPδ in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a low 5-year survival rate of only 13%. Despite intense research efforts, PDAC remains insufficiently understood. In part, this is attributed to opposing effects of key players being unraveled, including the stroma but also molecules that act in a context-dependent manner.

Carrier-Carrier Repulsion Limits the Conductivity of N-Doped Organic Semiconductors.

Molecular doping is a key strategy to enhance the electrical conductivity of organic semiconductors. Typically, the electrical conductivity shows a maximum value upon increased doping, after which the conductivity decreases. This decrease in conductivity is commonly attributed to unfavorable changes in the morphology.

Gemcitabine therapeutically disrupts essential SIRT1-mediated p53 repression in atypical teratoid/rhabdoid tumors.

Atypical teratoid/rhabdoid tumors (ATRTs) are highly malignant embryonal tumors of the central nervous system with a dismal prognosis. Using a newly developed and validated patient-derived ATRT culture and xenograft model, alongside a panel of primary ATRT models, we found that ATRTs are selectively sensitive to the nucleoside analog gemcitabine. Gene expression and protein analyses indicate that gemcitabine treatment causes the degradation of sirtuin 1 (SIRT1), resulting in cell death through activation of nuclear factor κB (NF-κB) and p53.

Transcriptome-based classification to predict FOLFIRINOX response in a real-world metastatic pancreatic cancer cohort.

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at metastatic stage and typically treated with fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX). Few patients benefit from this treatment. Molecular subtypes are prognostic in particularly resectable PDAC and might predict treatment response.

Structural Variants in the SMC1A Gene Associated With Near-Haploidy in Undifferentiated Pleomorphic Sarcomas.

Near-haploidization, that is, loss of one copy of most chromosomes, is a relatively rare phenomenon in most tumors, but is enriched among certain soft tissue sarcomas, including undifferentiated pleomorphic sarcoma (UPS). Presumably, near-haploidization can arise through many mechanisms. This study aimed to identify gene rearrangements that could cause near-haploidization.

Benefit of adjuvant chemotherapy on recurrence free survival per consensus molecular subtype in stage III colon cancer.

The consensus molecular subtype (CMS) classification divides colon tumors into four subtypes holding promise as a predictive biomarker. However, the effect of adjuvant chemotherapy on recurrence free survival (RFS) per CMS in stage III patients remains inadequately explored. With this intention, we selected stage III colon cancer (CC) patients from the MATCH cohort (n = 575) and RadboudUMC (n = 276) diagnosed between 2005 and 2018.

Predictive biomarkers for response to TGF- β inhibition in resensitizing chemo(radiated) esophageal adenocarcinoma.

Epithelial-mesenchymal transition (EMT) has been identified as a driver of therapy resistance, particularly in esophageal adenocarcinoma (EAC), where transforming growth factor beta (TGF-β) can induce this process. Inhibitors of TGF-β may counteract the occurrence of mesenchymal, resistant tumor cell populations following chemo(radio)therapy and improve treatment outcomes in EAC. Here, we aimed to identify predictive biomarkers for the response to TGF-β targeting.

Oncogenic and immunological targets for matched therapy of pediatric blood cancer patients: Dutch iTHER study experience.

Over the past 10 years, institutional and national molecular tumor boards have been implemented for relapsed or refractory pediatric cancer to prioritize targeted drugs for individualized treatment based on actionable oncogenic lesions, including the Dutch iTHER platform. Hematological malignancies form a minority in precision medicine studies. Here, we report on 56 iTHER leukemia/lymphoma patients for which we considered cell surface markers and oncogenic aberrations as actionable events, supplemented with ex vivo drug sensitivity for six patients.

Correction: A consensus molecular subtypes classification strategy for clinical colorectal cancer tissues.

This work presents a novel consensus molecular subtype (CMS) classifier for colorectal cancer (CRC), optimized for RNA-sequencing data stemming from degraded RNA of clinical formalin-fixed paraffin-embedded (FFPE) tissue samples (the CMSFFPE classifier).

Clinically unfavorable transcriptome subtypes of non-WNT/non-SHH medulloblastomas are associated with a predominance in proliferating and progenitor-like cell subpopulations.

The non-WNT/non-SHH (Grp3/Grp4) medulloblastomas (MBs) include eight second-generation subgroups (SGS; I-VIII) each with distinct molecular and clinical characteristics. Recently, we also identified two prognostically relevant transcriptome subtypes within each SGS MB, which are associated with unique gene expression signatures and signaling pathways. These prognostic subsets may be in connection to the intra-tumoral cell landscape that underlies SGS MB clinical-molecular diversity.

Pro-inflammatory T cells-derived cytokines enhance the maturation of the human fetal intestinal epithelial barrier.

Small intestine (SI) maturation during early life is pivotal in preventing the onset of gut diseases. In this study we interrogated the milestones of SI development by gene expression profiling and ingenuity pathway analyses. We identified a set of cytokines as main regulators of changes observed across different developmental stages.

A consensus molecular subtypes classification strategy for clinical colorectal cancer tissues.

Consensus Molecular Subtype (CMS) classification of colorectal cancer (CRC) tissues is complicated by RNA degradation upon formalin-fixed paraffin-embedded (FFPE) preservation. Here, we present an FFPE-curated CMS classifier. The CMSFFPE classifier was developed using genes with a high transcript integrity in FFPE-derived RNA.

USP44 Overexpression Drives a MYC-Like Gene Expression Program in Neuroblastoma through Epigenetic Reprogramming.

Neuroblastoma is an embryonic cancer that contributes disproportionately to death in young children. Sequencing data have uncovered few recurrently mutated genes in this cancer, although epigenetic pathways have been implicated in disease pathogenesis. We used an expression-based computational screen that examined the impact of deubiquitinating enzymes on patient survival to identify potential new targets.

MDM2 amplification in rod-shaped chromosomes provides clues to early stages of circularized gene amplification in liposarcoma.

Well-differentiated liposarcoma (WDLS) displays amplification of genes on chromosome 12 (Chr12) in supernumerary ring or giant marker chromosomes. These structures have been suggested to develop through chromothripsis, followed by circularization and breakage-fusion-bridge (BFB) cycles. To test this hypothesis, we compared WDLSs with Chr12 amplification in rod-shaped chromosomes with WDLSs with rings.