Biology subjects

Thrane, K.

Publications and source records attributed to Thrane, K..

6 recordsLinked to original sources

bioRxiv2026

Immune repertoire profiling reveals extensive clonal expansion of T and B cells in CXCL9-rich niches in sinonasal cancer

Sinonasal cancer (SNC) is a rare and aggressive head and neck cancer with limited therapeutic options and an incompletely defined immune microenvironment. Although histopathology remains central to clinical tumor evaluation, immune profiling typically requires tissue dissociation and therefore loses the spatial relationships that shape antitumor immunity. Here, we combined single-cell RNA-sequencing approaches, spatial transcriptomics and Spatial V(D)J, a technique we recently pioneered, to analyse the cellular, spatial, and clonal architecture of SNC. We found that SNC tumors were marked by a robust T cell infiltration, including substantial proportions of classical tissue resident memory (TRM) and exhausted (TExh) CD8+ T cells. This inflamed phenotype was accompanied by an immense infiltration of suppressive regulatory T (Treg) cells, which differentiated towards a Tbet+CXCR3+ phenotype. Spatially, expanded Treg, CD8 T and B cell clones concentrated within specialized peritumoral immune niches enriched for cancer-associated fibroblasts, CXCL9 tumor-associated macrophages and LAMP3IDO1 dendritic cells. T cell clones occupying these niches were clonally related to those infiltrating epithelial tumor regions, linking lymphoid hubs to the broader tumor immune response. Together, these data identify SNC as an inflamed but highly immunoregulatory tumor type and reveal a spatially organized clonal architecture in which suppressive and cytotoxic lymphocyte states coexist within CXCL9 myeloid niches.

immunology↗

bioRxiv2022

Spatial transcriptomics of T and B cell receptors uncovers lymphocyte clonal dynamics in human tissue.

The spatial distribution of lymphocyte clones within tissues is critical to their development, selection, and expansion. We have developed Spatial Transcriptomics of VDJ sequences (Spatial VDJ), which maps immunoglobulin and TR antigen receptors in human tissue sections. Spatial VDJ captures lymphocyte clones matching canonical T, B, and plasma cell distributions in tissues and amplifies clonal sequences confirmed by orthogonal methods. We confirm spatial congruency between paired receptor chains, develop a computational framework to predict receptor pairs, and link the expansion of distinct B cell clones to different tumor-associated gene expression programs. Spatial VDJ delineates B cell clonal diversity, class switch recombination, and lineage trajectories within their spatial context. Taken together, Spatial VDJ captures lymphocyte spatial clonal architecture across tissues, which could have important therapeutic implications. One-Sentence SummarySpatial transcriptomics-based technology co-captures T and B cell receptors within their anatomical niche in human tissue.

immunology↗

bioRxiv2022

Tumoroscope: a probabilistic model for mapping cancer clones in tumor tissues

Spatial and genomic heterogeneity of tumors is the key for cancer progression, treatment, and survival. However, a technology for direct mapping the clones in the tumor tissue based on point mutations is lacking. Here, we propose Tumoroscope, the first probabilistic model that accurately infers cancer clones and their high-resolution localization by integrating pathological images, whole exome sequencing, and spatial transcriptomics data. In contrast to previous methods, Tumoroscope explicitly addresses the problem of deconvoluting the proportions of clones in spatial transcriptomics spots. Applied to a reference prostate cancer dataset and a newly generated breast cancer dataset, Tumoroscope reveals spatial patterns of clone colocalization and mutual exclusion in sub-areas of the tumor tissue. We further infer clone-specific gene expression levels and the most highly expressed genes for each clone. In summary, Tumoroscope enables an integrated study of the spatial, genomic, and phenotypic organization of tumors.

cancer biology↗

bioRxiv2021

MapToCleave: high-throughput profiling of microRNA biogenesis in living cells

Previous large-scale studies have uncovered many features that determine the processing of microRNA (miRNA) precursors, however, they have been conducted in vitro. Here we introduce MapToCleave, a new method to simultaneously profile processing of thousands of distinct RNA structures in living cells. Our new in cell method captures essentially all the biogenesis features that have been discovered through near two decades of in vitro studies - providing support for both approaches. We find that miRNA precursors with a stable lower basal stem are more efficiently processed and also have higher expression in vivo in tissues from twenty animal species. We systematically compare the importance of known and novel sequence and structural features and test biogenesis of miRNA precursors from ten animal and plant species in human cells. Lastly, we provide evidence that the GHG motif better predicts processing when defined as a structure rather than sequence motif, consistent with recent cryo-EM studies. In summary, we apply a new screening assay in living cells to reveal the importance of lower basal stem stability for miRNA processing and in vivo expression.

molecular biology↗

bioRxiv2021

The spatial landscape of clonal somatic mutations in benign and malignant tissue

Defining the transition from benign to malignant tissue is fundamental to improve early diagnosis of cancer. Here, we provide an unsupervised approach to study spatial genome integrity in situ to gain molecular insight into clonal relationships. We employed spatially resolved transcriptomics to infer spatial copy number variations in >120 000 regions across multiple organs, in benign and malignant tissues. We demonstrate that genome-wide copy number variation reveals distinct clonal patterns within tumours and in nearby benign tissue. Our results suggest a model for how genomic instability arises in histologically benign tissue that may represent early events in cancer evolution. We highlight the power of an unsupervised approach to capture the molecular and spatial continuums in a tissue context and challenge the rationale for treatment paradigms, including focal therapy.

genomics↗

bioRxiv2020

The spatial landscape of gene expression isoforms in tissue sections

In situ capturing technologies add tissue context to gene expression data, with the potential of providing a greater understanding of complex biological systems. However, splicing variants and fulllength sequence heterogeneity cannot be characterized at spatial resolution with current transcriptome profiling methods. To that end, we introduce Spatial Isoform Transcriptomics (SiT), an explorative method for characterizing spatial isoform variation and sequence heterogeneity. We show in mouse brain how SIT can be used to profile isoform expression and sequence heterogeneity in different areas of the tissue. SiT reveals regional isoform switching of Plp1 gene between different layers of the olfactory bulb, and use of external single cell data allowed to nominate cell types expressing each isoform. Furthermore, SiT identifies differential isoform usage for several major genes implicated in brain function (Snap25, Bin1, Gnas) that we independently validated by in situ sequencing. SiT also provides for the first time an in-depth A-to-I RNA editing map of the adult mouse brain. Data exploration can be performed through an online resource (https://www.isomics.eu), where isoform expression and RNA editing can be visualized in a spatial context.

genomics↗