22938 results for "ega"

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• Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing

  High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, only half of which is explained. Previously, we performed germline exome sequencing on BRCA1 and BRCA2-negative HGSOC patients, revealing three proposed and 43 novel candidate genes enriched with rare loss-of-function variants. For validation, we undertook case-control analyses using genomic data from disease-free controls. This confirms enrichment for nearly all previously identified genes. Additionally, one-hundred-and-eleven HGSOC tumours from variant carriers were sequenced alongside other complementary studies, seeking evidence of biallelic inactivation as supportive evidence. PALB2 and ATM validate as HGSOC predisposition genes, with 6/8 germline carrier tumours exhibiting biallelic inactivation accompanied by characteristic mutational signatures. Among candidate genes, only LLGL2 consistently shows biallelic inactivation and protein expression loss, supporting it as a novel HGSOC susceptibility gene. The remaining candidate genes fail to validate. Integrating case-control analyses with tumour sequencing is thus crucial for accurate gene discovery in familial cancer studies.

  Study EGAS50000000770

• Transcriptome profiling of patient derived neural stem cells highlights the importance of CTNND2 and WNT signaling in early neuralization

  Loss of CTNND2/δ-catenin function is implicated in neurodevelopmental disorders, including Cri-du-chat syndrome, autism spectrum disorder and attention deficit hyperactivity disorder. CTNND2, the encoded protein, is crucial for the cadherin-catenin cell adhesion complex in the brain. However, the specific impact on neurodevelopment remains unclear. To investigate, we used neuroepithelial stem cells (NESCs) derived from patient-specific induced pluripotent stem cells (iPSCs) with loss of CTNND2. In monolayer cultures, we observed abnormal neural rosette formation and failure to establish stable neural stem cells. 3D organoid cultures confirmed delayed neurogenesis and slower growth in patient-derived iPSC lines. We have built a transcriptomic catalog and observed a dysregulation of the WNT signaling pathway linked to our observed cellular phenotypes. To validate we excluded the WNT activator CHIR99021 from the media, which partially rescued the transcriptomic and morphological phenotype of the patient neural induction. This study enhances our understanding of how CTNND2 loss affects early neurogenesis and neuronal maturation in patient specific cells.

  Study EGAS50000000323

• Whole exome sequencing of pre-invasive lung adenocarcinoma in non-smokers

  The prevalence of lung adenocarcinoma (LUAD) has increased sharply in East Asia. Early diagnosis leads to better survival rates, but this requires an improved understanding of the molecular changes during early tumorigenesis, particularly in non-smokers. We performed whole exome-sequencing and RNA-sequencing for samples from 94 East Asian patients with precancerous lesions (25 with atypical adenomatous hyperplasia [AAH]; 69 with adenocarcinoma in situ [AIS]) and 73 patients with early invasive lesions (minimally invasive adenocarcinoma [MIA]). Cellular analysis revealed that the activities of endothelial and stromal cells could categorize tumors into molecular subtypes within pathology-defined lesion types. These subtypes were linked with the advanced radiology-defined lesion type and coordinated with immune cell infiltration throughout the progression of LUAD. Characterization of these lesion types identified positively selected mutation patterns, and suggested that angiogenesis of the late-stage AIS type potentially contributes to tissue invasion of the MIA type. Our findings offer a novel resource that may help to improve early diagnosis and patient prognosis, and also suggest possible approaches for early disease interception.

  Study EGAS50000000438

• Anti-myeloperoxidase IgM B cells in anti-neutrophil cytoplasmic antibody-associated vasculitis

  Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a prototypic autoimmune disease, with a subset of AAV patients manifesting anti-myeloperoxidase (MPO) IgG. Patients with AAV respond positively to B cell-targeting and complement-targeting therapies, but disease flares are not uncommon. Here, by comparing samples from healthy individuals and MPO+ AVV patients, we show that B cell autoreactivity against MPO in the circulation of patients is dominated by CD27+IgM+ B cells whereas MPO-specific IgG+ cells are infrequent. Additionally, while naive anti-MPO-IgM B cells are present in both patients and controls and produce anti-MPO IgM upon stimulation, anti-MPO-IgM memory B cells and serum anti-MPO IgM are features of patients. Our results thus hint that defective elimination of B cell reactivity to MPO in the human repertoire, the presence of activated IgM+ anti-MPO B cells in disease, and a dominant role for anti-MPO IgM in complement activation, may all contribute to MPO+ AAV etiology and thereby serve as potential target for therapy.

  Study EGAS50000000753

• Copy number variations and fragmentation features in cell-free DNA predict response in advanced non-small cell lung cancer patients under anti-PD-(L)1 therapy

  Anti-PD-(L)1 therapy is routinely used in metastatic NSCLC. However, response rates vary and biomarkers predicting treatment efficacy are lacking. Liquid biopsies allow monitoring of residual disease during therapy. Residual circulating tumor DNA (ctDNA) after therapy represents a predictive marker for adverse outcome. Here, we assessed copy number variations (CNVs) in serial plasma samples of NSCLC patients receiving PD-(L)1 blockade. We profiled CNV and fragmentation features in 118 plasma samples of advanced NSCLC patients by low-coverage whole genome sequencing taken at baseline, after four therapy cycles and at disease progression. CNVs and fragment features (i.e., fragment length, end motifs, position) were significantly altered in patients compared to healthy donors. Furthermore, fragment length changes at baseline and residual CNVs after four therapy cycles correlated with short progression-free survival. Our results highlight the suitability of plasma-based CNV and fragment analysis for disease monitoring and as a predictive marker for response duration in NSCLC patients under anti-PD-(L)1 therapy.

  Study EGAS50000000441

• Gene expression adaptation of metastases to their host tissue

  The adaptation of metastatic cells to their host tissue critically determines the pathogenicity of a cancer and therefore patient survival. Yet, it remains elusive to what extent the host environment drives gene expression programs in metastatic cells. Here we identify adaptive mechanisms that enable metastases to establish themselves in a novel tissue context. We performed single-cell RNA-sequencing on malignant and benign tissue samples from untreated donors with colorectal adenocarcinoma and liver metastasis to deduce tissue adaptive expression patterns. A novel computational approach identified genes and pathways that consistently adapted to the host tissue at the transition from the primary tumor to the paired metastasis across donors. This analysis revealed that the majority of expression changes in the metastasis reflect an expression signature reminiscent of benign liver epithelial cells. Cellular processes adapting to the liver environment include basic cellular functions such as energy metabolism, as well as tissue-specific pathways such as the regulation of lipid metabolism by PPAR-α. These adaptations potentially increase the pathogenicity of the metastatic cells and may provide new therapeutic strategies.

  Study EGAS50000000817

• Timing and trajectory of BCR-ABL1 driven chronic myeloid leukaemia

  Mutation of some genes provide fitness advantages that drive uncontrolled cell proliferation, leading to clinical manifestations of cancer. The discovery of the Philadelphia chromosome in chronic myeloid leukaemia (CML) provided the very first such genetic link to cancer and the hypothesis that this lesion provided an abnormal growth advantage to cells. However, little is known about the trajectory to CML, the rate of BCR::ABL1 driven clonal expansion, and how this impacts on disease presentation. Here, using whole-genome sequencing of 1013 single-cell-derived colonies from patients with CML, we reconstruct phylogenetic trees of haematopoiesis in 9 patients aged 22 to 81 years at diagnosis. The expected intronic breaks in BCR and ABL1 were not always observed, and out-of-frame exonic breakpoints in BCR, requiring exon skipping to derive BCR::ABL1 fusion transcripts, were noted in several patients. Apart from ASXL1 and RUNX1 mutations, additional somatic mutations in myeloid genes were generally present only in wild-type cells and did not contribute to the CML clone. Using phylogenetic analysis, we infer sustained explosive growth attributed to BCR::ABL1 fusion, with clonal expansions beginning 3-14 years (Cl 2-16 years) before diagnosis and annual growth rates exceeding 70,000% per year in some young patients with the most recent and rapid clonal expansions. Mutation rate was higher in BCR::ABL1-positive cells than in wild-type counterparts, together with markedly shorter telomere lengths, reflecting their excessive cell division history. Clonal expansion rates inferred from phylogenetic trees were in line with mutational signature patterns and telomere attrition, and inversely correlated with the time to diagnosis. Whole genome sequencing of advanced phase CML was characterised by genomic evolution within BCR::ABL1-positive cells. Our findings highlight the oncogenic potency of a single BCR::ABL1 fusion and its capacity to drive fast clonal outgrowth to cancer. These data contrast with the early-in-life, slow, and sequential clonal trajectories typical of most cancers, such as Philadelphia-negative myeloproliferative neoplasms, solid organ malignancies, and patterns of clonal expansion in healthy tissue ageing.

  Dataset EGAD00001015473

• Synthetic - FEGA Sweden Heilsa synthetic dataset December 2023

  Synthetic - This submission contains a subset of a synthetic dataset derived from the project Heilsa Tryggvedottir - a Nordic collaboration on sharing sensitive human data. Heilsa Tryggvedottir is funded by the Nordic e-Infrastructure Collaboration (NeIC), the ELIXIR nodes of Finland, Norway, and Sweden, Computerome in Denmark, and the Estonian Scientific Computing Infrastructure (ETAIS). In the synthetic data creation process, it was attempted to strike a fine balance between the usability of the datasets (e.g. technical FEGA development, testing, user training, and basic bioinformatics) and compliance with GDPR. File names and file content (e.g. headers in fastq) are anonymized. Moreover, the X, Y, and mitochondrial sequences have been discarded from the original data since these data can be used for maternal, paternal, or ethnic origin tracing. The dataset does not follow natural haplotype distribution (inherent to imputation panels). The only inputs derived from real sequence data are variant distribution density per chromosome and learning sequencing error models. The synthetic dataset consists of two fastq files, a cram file, a vcf file, and two index files.

  Study EGAS50000000086

• Relation between transcriptome, karyotype and age in cases of sex chromosome aneuploidies.

  Why women live longer than men is still an open question in human biology. Sex chromosomes have been proposed to play a role in the observed sex gap in longevity, and the Y male chromosome has been suspected of having a potential toxic genomic impact on male longevity. It has been hypothesized that transposable element (TE) repression declines with age, potentially leading to detrimental effects such as somatic mutations and disrupted gene expression, which may accelerate the aging process. Given that the Y chromosome is rich in repeats, age-related increases in TE expression could be more pronounced in males, likely contributing to their reduced longevity compared to females. In this work, we first studied whether TE expression is associated with the number of sex chromosomes in humans. We analyzed blood transcriptomic data obtained from individuals of different karyotype compositions: 46,XX females (normal female karyotype), 46,XY males (normal male karyotype), as well as males with abnormal karyotypes, such as 47,XXY, and 47,XYY.

  Study EGAS50000001009

• Bulk and single-cell RNA-sequencing data from five lines of human iPSC-derived (hiPSC-derived) astrocytes (3 in-house and 2 commercial lines), both alone and in co-culture with neurons, to define the molecular response of astrocytes to misfolded alpha-synuclein

  RNA editing is a post transcriptional mechanism that targets changes in RNA transcripts to modulate innate immune responses. We report the role of astrocyte specific, ADAR1 mediated RNA editing in neuroinflammation in Parkinson’s disease. We generated hiPSC-derived astrocytes, neurons and co-cultures and exposed them to small soluble alpha-synuclein aggregates. Oligomeric alpha-synuclein triggered an inflammatory glial state associated with TLR activation, viral responses, and cytokine secretion. This reactive state resulted in loss of neurosupportive functions, and the induction of neuronal toxicity. Notably, interferon response pathways were activated leading to upregulation, and isoform switching of the RNA deaminase enzyme, ADAR1. ADAR1 mediates A-to-I RNA editing, and increases in RNA editing were observed in inflammatory pathways in cells, as well as in post-mortem human PD brain. Aberrant, or dysregulated, ADAR1 responses and RNA editing may lead to sustained inflammatory reactive states in astrocytes triggered by alpha-synuclein aggregation, and this may drive the neuroinflammatory cascade in Parkinson’s.

  Study EGAS50000000751

• Development of a fully human glioblastoma-in-brain-spheroid model for accelerated translational research

  In glioblastoma (GBM) the intricate interplay between tumor cells and the surrounding microenvironment plays a crucial role in tumor progression, invasion, and therapeutic resistance. So far, studying these interactions in a controlled and representative model system has been challenging. Here, we report the development of hGliCS, a human glioma-cortical spheroid model that allows the elucidation of the biology of GBM cells and their interactions with a human-specific brain-like microenvironment and neurons. GBM cells efficiently invade the cortical spheroids, forming a well-connected network of communicating cells. The heterogeneous cellular states of the GBM cells within this model closely resembled findings previously observed in glioblastoma patients and in mouse xenografts. We observed a transition from predominantly mesenchymal-like cells to heterotopic states with a high diversity. In contrast to the substantial changes observed in the tumor cell population, the impact of the GBM cells on the neurons was minimal. We further demonstrate the suitability of hGliCS to test compounds targeting tumor-specific neurobiological features.

  Study EGAS50000000757

• Linked-Read Whole Genome Sequencing Profiles Structural Variant Landscape of Gliomas with Barcode-Level Evidence

  Structural variants (SVs) play essential roles in glioma oncogenesis and offer prognostic insights, yet the SV landscape of gliomas has not been completely characterized due to previous technological limitations. To comprehensively profile the SV landscape of gliomas, we performed linked-read whole genome sequencing (LR-WGS) on 31 tumour samples from 20 glioma patients. Using barcode-level evidence, we validated known SVs and identified the presence of extrachromosomal DNA containing the EGFR sequence, which correlates with elevated EGFR expression. Additionally, we uncovered rare SVs affecting genes typically mutated by single nucleotide variants (SNVs), including those in the SWI/SNF chromatin remodeling complex. Our analysis also reveals selective chromosomal vulnerabilities to SVs, highlighting certain chromosomes as hotspots for SV accumulation. Collectively, our results demonstrate the utility of LR-WGS in accurately detecting SVs and thoroughly profiling SV landscapes using barcode-level evidence. The insights gained into the synergistic effects of SNVs and SVs on oncogenes further underscore the importance of integrating SV analysis when examining mutations in gliomas.

  Study EGAS50000000947

• Genome-wide analyses of cell-free DNA for therapeutic monitoring of patients with pancreatic cancer

  Determining response to therapy for patients with pancreatic cancer can be challenging. We evaluated methods for assessing therapeutic response using cell-free DNA (cfDNA) in plasma samples from 40 patients with metastatic pancreatic cancer as part of the CheckPAC trial (NCT02866383). Patients were evaluated before and after initiation of therapy using tumor-informed plasma whole-genome sequencing (WGMAF), and genome-wide cfDNA fragmentation profiles and repeat landscapes (ARTEMIS-DELFI). Of those assessed with WGMAF, molecular responders had a median overall survival (OS) of 319 days compared to 126 days for non-responders (HR=0.29, 95% CI=0.11–0.79, p=0.011). For ARTEMIS-DELFI, patients with low scores after therapy initiation had a longer median OS than patients with high scores (233 days versus 172 days, HR=0.12, 95% CI=0.046-0.31, p<0.0001). We validated ARTEMIS-DELFI in a separate cohort of 40 patients with pancreatic cancer who were part of the PACTO trial (NCT02767557). These analyses suggest that non-invasive mutation and fragmentation-based cfDNA approaches can identify therapeutic response of individuals with pancreatic cancer.

  Study EGAS50000000923

• Ancient tree-topologies and gene-flow processes among human lineages in Africa

  The deep history of human evolution in Africa remain intensely debated. We produced 73 novel high-quality whole genomes from 14 Central and Southern African populations with diverse cultural practices. With extensive simulations and machine-learning Approximate Bayesian Computation inferences, we reconstruct jointly their complex history of divergences and migrations. We find vast genome-wide diversity within and among populations, often uncorrelated with geography and cultural practices. This demonstrates the necessity to explicitly consider local genomic patterns, without merging samples indiscriminately into larger a priori categories, to reconstruct human evolutionary histories. We find that tree-like evolutions with long periods of drift between short periods of unidirectional gene-flow best explain the data, and that the lineage ancestral to Khoe-San populations diverged around 300,000 years ago from a lineage ancestral to rainforest hunter-gatherers and neighboring agriculturalists. We also find that short periods of ancient and recent gene-flow coincide with epochs of major ecological and cultural changes in Sub-Saharan Africa.

  Study EGAS50000001072

• DHODH is a synthetic-lethal vulnerability in BCOR-deficient acute myeloid leukemia

  Acute Myeloid Leukemia (AML) remains challenging to treat, especially in cases with mutations in the BCL-6 co- repressor (BCOR), which are associated with poor prognosis and chemo-resistance. In this study, we reveal a synthetic lethal interaction between BCOR and dihydroorotate dehydrogenase (DHODH). We demonstrate that BCOR-deficient cells have a heightened sensitivity to DHODH inhibitors such as brequinar and leflunomide, that are already in clinical use. We confirm that DHODH inhibition selectively induces cell death in BCOR-mutant cells in multiple cellular models, in malignant and non-malignant cells, through chemical and genetic manipulation. Interestingly, we find that the dependency on DHODH does not stem from its role in de novo pyrimidine biosynthesis disruption. Rather, DHODH’s role in the electron transport chain, essential for mitigating reactive oxygen species, may be the physiological vulnerability that pushes BCOR-mutant cells toward cell death when DHODH is inhibited. DHODH inhibitors could be repurposed as targeted therapies for BCOR-mutant tumors, offering a promising strategy for precision medicine in AML and other cancers.

  Study EGAS50000001108

• DHODH is a synthetic-lethal vulnerability in BCOR-deficient acute myeloid leukemia

  Acute Myeloid Leukemia (AML) remains challenging to treat, especially in cases with mutations in the BCL-6 co- repressor (BCOR), which are associated with poor prognosis and chemo-resistance. In this study, we reveal a synthetic lethal interaction between BCOR and dihydroorotate dehydrogenase (DHODH). We demonstrate that BCOR-deficient cells have a heightened sensitivity to DHODH inhibitors such as brequinar and leflunomide, that are already in clinical use. We confirm that DHODH inhibition selectively induces cell death in BCOR-mutant cells in multiple cellular models, in malignant and non-malignant cells, through chemical and genetic manipulation. Interestingly, we find that the dependency on DHODH does not stem from its role in de novo pyrimidine biosynthesis disruption. Rather, DHODH’s role in the electron transport chain, essential for mitigating reactive oxygen species, may be the physiological vulnerability that pushes BCOR-mutant cells toward cell death when DHODH is inhibited. DHODH inhibitors could be repurposed as targeted therapies for BCOR-mutant tumors, offering a promising strategy for precision medicine in AML and other cancers.

  Study EGAS50000001060

• KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia

  NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML). NUP98 FOs drive leukemogenesis through phase-separated condensate formation and maintenance of an active chromatin landscape at stem cell-associated genes in cooperation with epigenetic regulators. Here we show that MYST family histone acetyltransferase (HAT) complex proteins including KAT6A/MOZ, KAT7/HBO1, and the common KAT6A/7 complex subunit BRPF1 associate with NUP98 FOs on chromatin and within condensates. MYST HATs are molecular dependencies in NUP98-rearranged (NUP98-r) leukemia, and genetic inactivation or pharmacologic inhibition of Kat6a and Kat7 impairs NUP98-r cell fitness. KAT6A/7 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, KAT6A/7 inhibition decreased leukemic burden in multiple NUP98-r leukemia xenograft mouse models, synergized with Menin inhibitor treatment, and was efficacious in Menin inhibitor-resistant cells. In summary, we show that MYST family HATs are therapeutically actionable dependencies in NUP98-r AML.

  Study EGAS50000001075

• Anti-TIGIT antibody tiragolumab improves PD-L1 blockade via myeloid and Treg cells

  Tiragolumab, an anti-TIGIT antibody with an active IgG1/kappa Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (NCT03563716) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone1. However, there remains little consensus on the mechanism(s) of response with this combination2. We found that high baseline intratumoral macrophages and Tregs were associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation was associated with clinical benefit in patients receiving the combination treatment. In mouse tumor models, tiragolumab surrogate antibodies inflamed tumor-associated macrophages, monocytes, and dendritic cells through Fc gamma receptors (FcɣR), in turn driving anti-tumor CD8+ T cells from an exhausted effector-like state to a more memory-like one. These results uncover a mechanism of action by which TIGIT checkpoint inhibitors can remodel immunosuppressive tumor microenvironments, and suggest that FcɣR engagement is an important consideration in anti-TIGIT antibody development.

  Study EGAS50000000251

• Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in endometriod carcinomas

  The mammalian SWI/SNF (mSWI/SNF) family of chromatin remodelers govern cell type-specific chromatin accessibility and gene expression and assemble as three distinct complexes: canonical BAF (cBAF), Polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF). ARID1A and ARID1B are paralog subunits that specifically nucleate the assembly of cBAF complexes and are frequently dual deleted in highly aggressive differentiated endometrial carcinomas (DECs). Here, in cellular models and primary human tumors, we find that ARID1A/B-mediated cBAF loss results in increased ncBAF and PBAF biochemical abundance and function genome-wide to maintain the DEC oncogenic signature. Further, treatment of ARID1A/1B-mutant cell lines and PDX models in vivo with a clinical-grade SMARCA4/2 ATPase inhibitor, FHD-286, markedly attenuates cell proliferation and tumor growth, and synergizes with carboplatin-based chemotherapy. Taken together, these findings reveal the oncogenic contributions of shifted of mSWI/SNF family complex abundance and chromatin-level gene regulatory functions and suggest therapeutic utility of mSWI/SNF complex small molecule inhibitors in dedifferentiated endometrial carcinoma and other cBAF-disrupted cancer types.

  Study EGAS50000001004

• CNA differences between RNA-based subtypes of PDAC

  Pancreatic ductal adenocarcinomas (PDAC) have a dismal prognosis with a 5-year survival of <5%. Chemoresistance and recurrences, seen in approximately 70% of PDAC patients, may partly be explained by intratumor heterogeneity (ITH) through which tumors may develop ‘escape routes’. In the Pancreas Multibiopsy (PM)-project we have obtained multiple fragments from pancreatic and other peri-ampullary carcinomas in order to reveal potential ITH and identify genetic aberrations that predict outcome after surgery and response to chemotherapy. CNA-profiles were used to complement the characterization of liabilities in PDAC that we identified previously using RNAseq in the form of epithelial, secretory, compound pancreatic, and mesenchymal subgroups that showed survival outcomes. Comparison of CNA-profiles between these transcriptomics-based subgroups (with 8, 3, 6, and 6 tumors respectively per group) showed differences, ranging from ‘quiet’(i.e. hardly any CNA) to ‘wild’(i.e. lots of CNA), but these were not statistically significant (Chi2 0.09). When differentiating between the classical and basal-like molecular subtypes of PDAC differences in CNA (high or low) were even less statistically significant (Chi2 0.292).

  Study EGAS50000001218

• Spatial transcriptomics analysis of triple negative breast cancers

  While triple negative breast cancer (TNBC) is known to be heterogeneous at the genomic and transcriptomic levels, spatial information on tumor organization and cell composition is still lacking. Here, we investigated TNBC tumor architecture including its microenvironment using spatial transcriptomics on a series of 92 patients. We performed an in-depth characterization of tumor and stroma organization and composition using an integrative approach combining histomorphological and spatial transcriptomics. Furthermore, a detailed molecular characterization of tertiary lymphoid structures led to identify a gene signature strongly associated to disease outcome and response to immunotherapy in several tumor types beyond TNBC. A stepwise clustering analysis identified nine TNBC ecotypes, further validated in external datasets. Several ecotypes were associated with disease outcome and characterized by potentially actionable features. In this work, we provideThis is the largest TNBC series providing a comprehensive insight into the complexity of TNBC ecosystem with potential clinical relevance, opening avenues for treatment tailoring including immunotherapy. All the processed data needed to replicate the results from the publication (counts, images, clinical data, etc) are available on Zenodo: https://zenodo.org/records/14204217

  Study EGAS50000000475

• Adaptive Therapy Exploits Fitness Deficits in Chemotherapy-Resistant Ovarian Cancer to Achieve Long-Term Tumor Control Open Access

  Drug resistance results in poor outcomes for cancer patients. Adaptive therapy is a potential strategy to address drug resistance that exploits competitive interactions between sensitive and resistant subclones. Here, we showed that adapting carboplatin dose according to tumor response (adaptive therapy) significantly prolonged survival of murine ovarian cancer models compared to standard carboplatin dosing, without increasing mean daily drug dose or toxicity. Platinum resistant ovarian cancer cells exhibited diminished fitness when drug was absent in vitro and in vivo, which caused selective decline of resistant populations due to reduced proliferation and increased apoptosis. Conversely fitter, sensitive cells re-grew when drug was withdrawn. Using a bioinformatics pipeline that exploits copy number changes to quantify the emergence of treatment resistance, analysis of cell‐free DNA obtained longitudinally from ovarian cancer patients during treatment showed subclonal selection through therapy, and measurements of resistant population growth correlated strongly with disease burden. These preclinical findings pave the way for future clinical testing of personalized adaptive therapy regimens tailored to the evolution of carboplatin resistance in individual ovarian cancer patients.

  Study EGAS50000001142

• The brain neurovascular epigenome and its association with dementia

  Cerebral small vessel disease (SVD) is frequently comorbid with Alzheimer’s disease (AD) and vascular brain endothelial cells (BECs) are enriched for the expression of genes associated with AD genetic risk. However, the gene regulatory landscapes of neurovascular cells and their intersection with genetic risk for disease remains unexplored. Here we have generated gene regulomes for human BECs, mural cells and other brain cell types to show that AD heritability is primarily immune-related and that it shows modest enrichment in BECs. By contrast, genetic risk for SVD is enriched across cells of the neurovascular unit, including astrocytes. Enhancer-to-gene interactomes implicate amyloid processes in both AD and SVD, though the risk genes are mostly distinct for the two disorders. Motifs for putative partners of lineage transcription factors in microglia and BECs were enriched for AD and SVD variants at genes linked to disease pathways. Gene prioritization and enrichment analyses further identified potential repurposable drugs for AD. Our findings highlight novel regulatory mechanisms and therapeutic targets within the neurovascular system.

  Study EGAS50000001160

• Human liver cholangiocyte organoids capture the heterogeneity of in vivo human liver ductal epithelium

  Human liver ductal epithelium is morphologically, functionally and transcriptionally heterogeneous. However, understanding the dynamics within human biliary/ductal epithelium has been hampered by the absence of an in vitro system that fully mimics its complex cellular heterogeneity. Here, we found that the human liver cholangiocyte (ductal-cell) organoids we previously published (Huch et al., 2015) are fairly homogenous and do not retain the cellular heterogeneity of the in vivo human biliary/ductal epithelium. Inspired by the knowledge of the in vivo niche, we refined our previous organoid culture medium to fully capture the cellular heterogeneity of the human ductal epithelium. We employed this refined system to analyse the interactions and relationships between the different human biliary epithelial cell states and discovered that acquiring a bipotent ductal cell state is necessary for differentiating the human ductal epithelium into functional hepatocyte-like cells. Our improved cholangiocyte organoid model represents a new platform to investigate cell plasticity and duct-to-hepatocyte differentiation in human liver.

  Study EGAS50000001000

• Plasma cell‐Free transcriptome profiling in chronic liver disease

  Chronic liver disease (CLD) encompasses a wide range of hepatic disorders that progressively compromise liver function. In order to support the development of non-invasive diagnostic tools and improve patient stratification, we generated a high-throughput extracellular RNA sequencing dataset from blood plasma samples collected from patients at various stages of liver disease. Samples were obtained from two independent cohorts of 112 (cohort 1) and 489 (cohort 2) patients using standardized collection and processing protocols, and profiled using total RNA sequencing (SMARTer Stranded Total RNA-Seq Kit v3 - Pico Input Mammalian), resulting in 112 and 820 extracellular transcriptomic profiles for cohort 1 and 2, respectively. This dataset is provided with full documentation of the preprocessing analysis pipeline and accompanying metadata, enabling its use as an independent validation cohort for biomarker discovery and as a complementary resource for integrative multi-omics studies, even in cases with incomplete data modalities. The publicly available resource is intended to facilitate reproducibility and foster further research in the field of liver disease diagnostics

  Study EGAS50000000545