Biology subjects

van den Oord, J.

Publications and source records attributed to van den Oord, J..

3 recordsLinked to original sources

bioRxiv2022

A TCF4/BRD4-dependent regulatory network confers cross-resistance to targeted and immune checkpoint therapy in melanoma

Primary resistance drastically limits the clinical success of immune checkpoint blockade (ICB) in melanoma. Resistance to ICB may also develop when tumours relapse after targeted therapy. To identify cancer cell-intrinsic mechanisms driving resistance to ICB, we generated single-cell RNA-sequencing (scRNA-seq) data from a prospective longitudinal cohort of patients on ICB therapy, including an early time point obtained after only one cycle of treatment. Comparing these data with murine scRNA-seq datasets, we established a comprehensive view of the cellular architecture of the treatment-naive melanoma ecosystem, and defined 6 evolutionarily conserved melanoma transcriptional metaprograms (Melanocytic or MEL, Mesenchymal-like or MES, Neural Crest-like, Antigen Presentation, Stress (hypoxia response) and Stress (p53 response)). Spatial multi-omics revealed a non-random geographic distribution of cell states that is, at least partly, driven by the tumour microenvironment. The single-cell data allowed unambiguous discrimination between melanoma MES cells and cancer-associated fibroblasts both in silico and in situ, a long-standing challenge in the field. Importantly, two of the melanoma transcriptional metaprograms were associated with divergent clinical responses to ICB. While the Antigen Presentation cell population was more abundant in tumours from patients who exhibited a clinical response to ICB, MES cells were significantly enriched in early on-treatment biopsies from non-responders, and their presence significantly predicted lack of response. Critically, we identified TCF4 (E2-2) as a master regulator of the MES program and suppressor of both MEL and Antigen Presentation programs. Targeting TCF4 expression in MES cells either genetically or pharmacologically using a bromodomain inhibitor increased immunogenicity and sensitivity to targeted therapy. This study describes an increasingly complex melanoma transcriptional landscape and its rapid evolution under ICB. It also identifies a putative biomarker of early response to ICB and an epigenetic therapeutic strategy that increases both immunogenicity of ICB-refractory melanoma and their sensitivity to targeted therapy.

cancer biology↗

bioRxiv2018

High-dimensional single cell-analysis of lymphocytic activation in melanoma

In melanoma, the lymphocytic infiltrate is a prognostic parameter classified morphologically into "brisk", "non-brisk" and "absent" entailing a functional association that has never been proved. Recently, it has been shown that lymphocytic populations can be very heterogeneous, and that anti-PD-1 immunotherapy supports activated T cells. Here, we characterize the immune landscape in primary melanoma by high-dimensional single cell multiplex analysis in tissue sections (MILAN technique) followed by image analysis, RT-PCR and shotgun proteomics. We observed that the brisk and non-brisk patterns are heterogeneous functional categories that can be further sub-classified into active, transitional or exhausted. The classification of primary melanomas based on the functional paradigm also shows correlation with spontaneous regression, and an improved prognostic value than that of the brisk classification. Finally, the main inflammatory cell subpopulations that are present in the microenvironment associated with activation and exhaustion and their spatial relationships are described using neighbourhood analysis.

cancer biology↗

bioRxiv2017

SCENIC: Single-Cell Regulatory Network Inference And Clustering

Single-cell RNA-seq allows building cell atlases of any given tissue and infer the dynamics of cellular state transitions during developmental or disease trajectories. Both the maintenance and transitions of cell states are encoded by regulatory programs in the genome sequence. However, this regulatory code has not yet been exploited to guide the identification of cellular states from single-cell RNA-seq data. Here we describe a computational resource, called SCENIC (Single Cell rEgulatory Network Inference and Clustering), for the simultaneous reconstruction of gene regulatory networks (GRNs) and the identification of stable cell states, using single-cell RNA-seq data. SCENIC outperforms existing approaches at the level of cell clustering and transcription factor identification. Importantly, we show that cell state identification based on GRNs is robust towards batch-effects and technical-biases. We applied SCENIC to a compendium of single-cell data from the mouse and human brain and demonstrate that the proper combinations of transcription factors, target genes, enhancers, and cell types can be identified. Moreover, we used SCENIC to map the cell state landscape in melanoma and identified a gene regulatory network underlying a proliferative melanoma state driven by MITF and STAT and a contrasting network controlling an invasive state governed by NFATC2 and NFIB. We further validated these predictions by showing that two transcription factors are predominantly expressed in early metastatic sentinel lymph nodes. In summary, SCENIC is the first method to analyze scRNA-seq data using a network-centric, rather than cell-centric approach. SCENIC is generic, easy to use, and flexible, and allows for the simultaneous tracing of genomic regulatory programs and the mapping of cellular identities emerging from these programs. Availability: SCENIC is available as an R workflow based on three new R/Bioconductor packages: GENIE3, RcisTarget and AUCell. As scalable alternative to GENIE3, we also provide GRNboost, paving the way towards the network analysis across millions of single cells.

bioinformatics↗