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• Treatment stratification and biomarker validation using patient-derived head and neck cancer organoids

  Background Organoids are three-dimensional structures that can be grown from patient-derived material including carcinomas. These in vitro models can be cryopreserved to generate “living” biobanks that reflect patient heterogeneity. Head and neck cancer (HNC) is a collective term used for tumors arising in the head and neck area, including squamous cell carcinomas (HNSCC) and adenocarcinoma of the salivary gland. Methods to culture patient-derived HNC organoids have previously been described. Methods Organoids were derived from resection or biopsy material of patients included between 2016 and 2022. Organoids were characterised with immunohistochemistry and whole exome sequencing (WES) and exposed to chemo-, radio- and targeted-therapies. CRISPR/Cas9-based gene editing was applied to validate proposed biomarkers. Results We have extended our previously published organoid biobank to a total of 110 organoid models, some of which were characterised by histology and WES. Organoids recapitulated both single nucleotide variants and copy number alterations as found in patient HNSCC samples. Organoid and patient response to radiotherapy (RT; primary (n=6) and adjuvant (n=15)) could be compared in 21 HNC cases. In the adjuvant RT group, organoids derived from patients that relapsed were more resistant to RT in vitro, showing potential for guiding treatment options in this subset of patients. Conclusion Taken together, these results indicate illustrate the potential of organoids as a diagnostic tool in personalised medicine for HNC and indicate the potential of this technology for biomarker discovery and validation within the context of relevant patient heterogeneity.

  Study EGAS00001007076

• Whole Exome Sequencing data of six chRCC tumors corresponding to three patients

  Mammalian target of rapamycin (mTOR) is a central regulator of mammalian metabolism and physiology. Aberrant hyperactivation of the mTOR pathway promotes tumor growth and metastasis, and can also promote tumor resistance to chemotherapy and cancer drugs; this makes mTOR an attractive cancer therapeutic target. mTOR inhibitors have been approved to treat cancer; however, the mechanisms underlying drug sensitivity remain poorly understood. Here, whole exome sequencing of three chromophobe renal cell carcinoma (chRCC) patients with exceptional mTOR inhibitor sensitivity revealed that all three patients shared somatic mutations in the deubiquitinase USP9X. The clonal characteristics of the mutations, which were amassed by studying multiple patients’ primary and metastatic samples from various years, together with the low USP9X mutation rate in unselected chRCC series, reinforced a causal link between USP9X and mTOR inhibitor sensitivity. Rapamycin treatment of USP9X-depleted HeLa and renal cancer 786-O cells, along with the pharmacological inhibition of USP9X, confirmed that this protein plays a role in patients’ sensitivity to mTOR inhibition. USP9X was not found to exert a direct effect on mTORC1, but subsequent ubiquitylome analyses identified p62 as a direct USP9X target. Increased p62 ubiquitination and the augmented rapamycin effect upon bortezomib treatment, together with the results of p62 and LC3 immunofluorescence assays, suggested that dysregulated autophagy in USP9X-depleted cells can have a synergistic effect with mTOR inhibitors. In summary, we show that USP9X constitutes a potential novel marker of sensitivity to mTOR inhibitors in chRCC patients, and represents a clinical strategy for increasing the sensitivity to these drugs.

  Study EGAS00001007104

• Pharmacogenomic Analysis Reveals New Therapeutic Options for Pleural Mesothelioma

  Background: Pleural mesothelioma (PM) urgently requires novel effective treatments. Drug repurposing is a relevant strategy to discover new therapeutic options among well-known drugs used in clinical practice. This study aimed to identify new therapies in the context of molecular heterogeneity of PM. Methods: We performed a multi-omics study of the largest cohort of patient-derived primary PM cell lines (n=58) to date, using whole exome sequencing, RNA sequencing and methylome analysis. We also conducted a large-scale drug screening of over 1300 compounds on a subset of cell lines (n=11), as well as an extension screen (n=48) for selected drugs of interest. The best candidates were validated using 3D culture and mouse models. Results: We demonstrated that the molecular landscape of the cell lines cohort recapitulates the main findings in tumours and revealed new specific features of PM. The large-scale drug screening and subsequent validations highlighted notably strong sensitivity to entinostat and fluvastatin. Importantly, both compounds displayed same efficacy in 2D and 3D culture models and single treatment prolonged survival in vivo similarly or even better than standard chemotherapy. Strikingly, combining entinostat treatment with anti-PD1 led to cures in some mice and immunized them against tumour cells. Conclusions: Among several candidates, we identified entinostat, notably in combination with immune checkpoint inhibitor, and to a lesser extent fluvastatin, as promising therapeutic options for patients. We believe our study provides a valuable resource that could contribute to advances in the field and warrants further clinical investigation.

  Study EGAS00001007866

• Targeting vulnerabilities in IDH mutant tumours: The model matters WES study

  Introduction: Synthetic lethal interactions with IDH1 and IDH2 (IDH) mutations were identified in non-endogenous IDH mutant (IDHmut) AML and glioma models, but are absent in endogenous IDHmut chondrosarcoma cell lines. The translation into successful clinical applications has remained challenging, implying artificially created models do not fully recapitulate endogenous IDHmut tumour biology. The aim of this study was to elucidate if the model system is indeed an important factor to consider when studying therapeutic vulnerabilities in IDHmut tumours. Methods: Vector-based and CRISPR-Cas9 approaches were used to introduce or revert the IDH1 mutation in chondrosarcoma cell lines. These isogenic cell line pairs were used to examine the presence of known therapeutic vulnerabilities and their underlying biological mechanisms. Results: Vector-based IDHmut chondrosarcoma models showed the previously reported synthetic lethal interactions, but these treatment sensitivities were absent in the CRISPR-edited models. Interestingly, not all vector-based IDHmut cell lines displayed the same therapeutic vulnerabilities. Differences in treatment response were associated with multiple factors, including IDHmut protein expression and D-2-HG levels, in line with the fact that therapeutic vulnerabilities could be induced in the CRISPR-edited models by enhancing D-2-HG levels. Conclusion: Our findings demonstrate that synthetic lethal interactions observed in vector-based models are often a consequence of IDHmut protein overexpression and supra-physiological D-2-HG levels. These results highlight that relying on artificially created IDHmut models may lead to the identification of therapeutic vulnerabilities that are not present in IDHmut tumours, potentially explaining the poor translation of preclinical findings to clinical trials.

  Study EGAS50000001870

• Targeting vulnerabilities in IDH mutant tumours: The model matters RNAseq study

  Introduction: Synthetic lethal interactions with IDH1 and IDH2 (IDH) mutations were identified in non-endogenous IDH mutant (IDHmut) AML and glioma models, but are absent in endogenous IDHmut chondrosarcoma cell lines. The translation into successful clinical applications has remained challenging, implying artificially created models do not fully recapitulate endogenous IDHmut tumour biology. The aim of this study was to elucidate if the model system is indeed an important factor to consider when studying therapeutic vulnerabilities in IDHmut tumours. Methods: Vector-based and CRISPR-Cas9 approaches were used to introduce or revert the IDH1 mutation in chondrosarcoma cell lines. These isogenic cell line pairs were used to examine the presence of known therapeutic vulnerabilities and their underlying biological mechanisms. Results: Vector-based IDHmut chondrosarcoma models showed the previously reported synthetic lethal interactions, but these treatment sensitivities were absent in the CRISPR-edited models. Interestingly, not all vector-based IDHmut cell lines displayed the same therapeutic vulnerabilities. Differences in treatment response were associated with multiple factors, including IDHmut protein expression and D-2-HG levels, in line with the fact that therapeutic vulnerabilities could be induced in the CRISPR-edited models by enhancing D-2-HG levels. Conclusion: Our findings demonstrate that synthetic lethal interactions observed in vector-based models are often a consequence of IDHmut protein overexpression and supra-physiological D-2-HG levels. These results highlight that relying on artificially created IDHmut models may lead to the identification of therapeutic vulnerabilities that are not present in IDHmut tumours, potentially explaining the poor translation of preclinical findings to clinical trials.

  Study EGAS50000001871

• Clinical relevance of somatic copy-number alterations in plasma circulating tumor DNA from advanced EGFR-mutated NSCLC patients treated with osimertinib

  Background: Somatic copy-number alterations (SCNAs) are associated with drug resistance in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) treated with EGFR-tyrosine kinase inhibitors (TKIs). The purpose of our study was to assess the clinical relevance and development of genome-wide SCNAs in plasma circulating tumor DNA (ctDNA) under osimertinib therapy.Methods: We included 43 patients with advanced EGFR T790M-positive lung adenocarcinoma who were treated with osimertinib after progression under previous EGFR-TKI therapy. We performed genomic profiling of ctDNA in plasma samples from each patient obtained pre-osimertinib and after patients developed resistance to osimertinib. SCNAs were detected by shallow whole-genome plasma sequencing and EGFR mutations were assessed by droplet digital PCR.Results: SCNAs in resistance-related genes (rrSCNAs) were detected in 10 out of 39 (25.6%) evaluable patients before start of osimertinib. The presence of rrSCNAs in plasma before initiation of osimertinib therapy was associated with a lower response rate to osimertinib (50% versus 86%, p=0.02) and was an independent predictor for shorter progression-free survival (adjusted HR 3.26, 95% CI 1.37-7.75, p=0.008) and overall survival (adjusted HR 2.41, 95% CI 1.09-5.34, p=0.03).Conclusions: Genomic profiling of plasma ctDNA is clinically relevant and affects the efficacy and clinical outcome of osimertinib. Our approach allows comprehensive assessment of SCNAs in plasma samples of lung adenocarcinoma patients and may help to guide genotype-specific therapeutic strategies in the future.

  Study EGAS00001004539

• A Single-Cell and Spatial Atlas of Early Human Olfactory Development

  The human nasal region is a complex structure derived from neural crest and placodal lineages, but its development remains poorly understood due to limited fetal tissue access and its intricate architecture. To address this, we created a single-nucleus and spatial transcriptomic atlas of the human fetal nasal region using tissue from 10 fetuses between 7 and 12 post-conceptional weeks. Single-nucleus RNA sequencing (snRNA-seq) revealed 34 distinct cell types, including epithelial, cartilaginous, immune, neuronal, glial, muscular, and vascular cells. By integrating snRNA-seq with multiplexed error-robust fluorescence in situ hybridization (MERFISH), we tracked dynamic changes in cell composition and gene expression over time in the olfactory epithelium (OE) and surrounding nasal regions. We identified novel markers of olfactory sensory neuron development and key pathways regulating epithelial patterning and OE morphogenesis. Notably, we observed early molecular signatures consistent with the "one neuron-one receptor" model, with spatially organized expression of 171 olfactory receptor genes. Together, this study presents the first integrated molecular and spatial framework of early human nasal development. It offers an unprecedented molecular blueprint of olfactory system formation and serves as a foundational resource for embryologists and developmental biologists studying sensory neurogenesis, epithelial patterning, and congenital disorders.

  Dataset EGAD50000001712

• A Cultured Leukemia Stem Cell Model Enables Validation of CDK6 as a Stemness Target Against Acute Myeloid Leukemia

  Acute myeloid leukemia (AML) represents a group of aggressive hematological malignancies, the clinical management of which is made challenging due to the persistence of rare and therapy resistant leukemia stem cells (LSCs) which serve as a source of disease relapse and poor outcomes. There are currently a paucity of methods to reliably enrich and study LSCs, hindering the development of therapies that specifically target LSCs. In this study, we deeply characterize the OCI-AML8227 culture model, which maintains a functional stemness hierarchy originating from its highly primitive CD34⁺CD38⁻ cells, to elucidate LSC biology and uncover LSC-specific therapeutic vulnerabilities. We analyzed both bulk and single-cell proteomics, transcriptomics, and epigenomics to generate a LSC protein-protein interaction network, which was then integrated with an LSC-focused small molecule screen using this model. From these findings, CDK6 was discovered as a therapeutic vulnerability specific to LSCs, which was validated in findings from the BEAT-AML cohort and a patient-derived xenograft (PDX) panel of AML samples through palbociclib treatment. Taken together, our studies validate CDK6 as a druggable vulnerability in LSCs, and authenticate OCI-AML8227 cells as a LSC target discovery engine.

  Dataset EGAD50000001156

• PPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysm in humans

  Rupture of intracranial aneurysms (IAs) leads to subarachnoid hemorrhage (SAH), a sudden-onset disease often causing severe disability or death. Using whole exome sequencing, we identified significant enrichment of rare, deleterious mutations in PPIL4 in both index and familial IA cases. Ppil4 depletion causes intracerebral hemorrhage, defects in cerebrovascular morphology, and impaired Wnt signaling in vivo. Wild type, but not IA-mutant PPIL4, potentiates Wnt signaling by binding JMJD6, a known angiogenesis regulator and Wnt activator. These findings identify a novel PPIL4-dependent Wnt signaling mechanism involved in brain-specific angiogenesis and maintenance of cerebrovascular integrity, and implicate PPIL4 gene variation in the pathogenesis of human IA.

  Study EGAS00001005518

• sWGS of HGSOC samples for fixative comparison study

  Shallow whole-genome sequencing of samples from the study "Methanol-based fixation is superior to buffered formalin for next-generation sequencing of DNA from clinical cancer samples". DNA from each sample (100ng) was sheared on Covaris S220 (Covaris): duty cycle - 10%, intensity -5.0, bursts per sec - 200, duration - 300 sec, mode - frequency sweeping, power - 23V, temperature -5:5 C to 6 C, water level - 13. Libraries were prepared with the TruSeq Nano DNA LT Sample Prep Kit (Illumina) using a modi?ed protocol - Sample Puri?cation Beads were replaced by Agencourt AMPure XP beads (Beckman Coultier) and size selection after the End Repair was done to remove only the short fragments. Quality and quantity for contructed libraries were assessed with DNA 7500 kit on Agilent 2100 Bioanalyzer and with Kapa Quanti?cation kit (KAPA Biosystems) on 7900HT Fast Real-Time PCR System (Applied Biosystems) according to the supplier's recommendations, respectively. Libraries from 18 barcoded samples were pooled together in equimolar amounts and each pool was loaded on a single lane of a HiSeq Single End Flowcell (Illumina), followed by cluster generation on a cBot (Illumina) and sequencing on a HiSeq 2500 (Illumina) in a single-read 50bp mode. Reads were aligned using bwa-mem v0.7.12-r1039 to the 1000 genomes version of human genome build GRCh37. Picard (http://picard.sourceforge.net) was used to remove duplicate reads.

  Dataset EGAD00001001938