Biology subjects

Borras, D. M.

Publications and source records attributed to Borras, D. M..

3 recordsLinked to original sources

bioRxiv2025

The molecular landscape of polycystic kidneys is marked by common alterations in purine metabolism

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease. Cysts develop through dedifferentiation of tubular epithelial cells, but the sequence of molecular events and their relative importance remain unclear. To address this gap in knowledge, 40 cysts from 4 ADPKD kidneys and 4 microcystic tissues were mapped on transcriptomic and histological level. Cyst were heterogenous and we identified 6 cystic subclusters with 2 deviations from the main trajectory, dependent on the rate of interstitial remodeling, inflammation and dedifferentiation. Loss of proximal tubular marker gene expression was more pronounced compared to those of other tubular segments. Altered expression of metabolic pathways was consistent among the cysts, which was further analyzed in human and mouse cell lines. Purine metabolism was similarly altered in all ADPKD cell lines, and its modulation with azathioprine suppressed cyst formation in vitro. In conclusion, by focusing on common altered pathways in cysts and cell models, we have identified purine metabolism as a novel potential target in ADPKD.

molecular biology↗

bioRxiv2021

Immunogenomic, single-cell and spatial dissection of CD8+T cell exhaustion reveals critical determinants of cancer immunotherapy

Tumoural-CD8+T cells exhibit exhausted or dysfunctional states. Contrary to immunotherapy-responsive exhausted-CD8+T cells, the clinical features of dysfunctional-CD8+T cells are disputed. Hence, we conducted large-scale multi-omics and multi-dimensional mapping of CD8+T cell-states across multiple cancer patient-cohorts. This identified tumour-specific continuum of CD8+T cell-states across 6 human cancers, partly imprinted by organ-specific immuno-modulatory niches. Herein, melanoma and glioblastoma enriched prototypical exhausted (CD8+TEXT) and severely-dysfunctional (CD8+TSDF) states, respectively. Contrary to CD8+TEXT, CD8+TSDF displayed transcriptomic and epigenetic effector/cytolytic dysfunctions, and dysregulated effector/memory single-cell trajectories, culminating into maladaptive prodeath stress and cell-cycle defects. Suboptimal antigen-priming underscored CD8+TSDF, which was distinct from immune-checkpoints "rich" CD8+TEXT, reflecting chronic antigen-stimulation. Continuum variation also existed on tumour spatial-level, with convergent (CD8+TEXT-supportive vascular regions) and divergent features (dysfunctional CD4+T::CD8+TSDFcell-to-cell interactions) between melanoma and glioblastoma. Globally, IFN{gamma}-IL2 disparities, paucity of intra-tumoural CD4+/CD8+T cells, and myeloid TGF{beta}/wound healing responses, distinguished CD8+TSDF-landscape. Within immuno-oncology clinical-trials, anti-PD1 immunotherapy failed to "reinvigorate" CD8+TSDF-landscape, and instead facilitated effector-dysfunction and TGF{beta}/wound healing. However, cellular immunotherapies (dendritic cell-vaccines, adoptive T-cell therapy) ameliorated assorted CD8+TSDF-landscape disparities, highlighting a roadmap for anti-glioblastoma multimodal-immunotherapy. Collectively, our study comprehensively expands clinical-knowledge on CD8+T cell-exhaustion and suggests that tumour-specific, pre-existing CD8+TEXT/TSDF-states, determine immunotherapy-responses.

immunology↗

bioRxiv2021

CRISPR activation screening identifies VGLL3 and GATA2 as transcriptional regulators of PD-L1

The PD-L1/2 - PD-1 immune checkpoint is essential for the proper induction of peripheral tolerance and limits autoimmunity, whereas tumor cells exploit their expression to promote immune evasion. Many different cell types express PD-L1/2, either constitutively or upon stimulation, but the factors driving this expression are often not defined. Here, using genome-wide CRISPR-activation screening, we identified three factors that upregulate PD-L1 expression; GATA2, MBD6, and VGLL3. GATA2 and VGLL3 act as transcriptional regulators and their expression induced PD-L1 in many different cell types. Conversely, loss of VGLL3 impaired IFN{gamma}-induced PD-L1/2 expression in keratinocytes. Mechanistically, by performing a second screen to identify proteins acting together with VGLL3, we found that VGLL3 forms a complex with TEAD1 and RUNX1/3 to drive expression of PD-L1/2. Collectively, our work identified a new transcriptional network controlling PD-L1/2 expression and suggests that VGLL3, in addition to its known role in the expression of pro-inflammatory genes, can balance inflammation by upregulating the anti-inflammatory factors PD-L1 and PD-L2.

immunology↗