Biology subjects

Pircher, A.

Publications and source records attributed to Pircher, A..

3 recordsLinked to original sources

bioRxiv2024

Dissecting heterogeneity of tumor microenvironment in colorectal cancer using high-resolution single-cell atlas

The immune composition of the tumor microenvironment (TME) has a major impact on the therapeutic response and clinical outcome in patients with colorectal cancer (CRC). Here, we comprehensively characterize the TME at the single-cell level by first building a large-scale atlas that integrates 4.27 million single cells from 1,670 patient samples. We then complemented the atlas with single-cell profiles from four CRC cohorts with 266 patients, including cells with low mRNA content, spatial transcriptional profiles from 3.7 million cells, and protein profiles from 0.7 million cells. The analysis of the atlas allows refined tumor classification into four immune phenotypes: immune desert, B cell enriched, T cell enriched, and myeloid cell enriched subtypes. Within the myeloid compartment we uncover distinct subpopulations of neutrophils that acquire new functional properties in blood and in the TME, including anti-tumorigenic capabilities. Further, spatial multimodal single-cell profiling reveals that neutrophils are organized in clusters within distinct functional niches. Finally, using an orthotopic mouse model we show that cancer-derived systemic signals modify neutrophil production in the bone marrow, providing evidence for tumor-induced granulopoiesis. Our study provides a big data resource for the CRC and suggests novel therapeutic strategies targeting neutrophils.

bioinformatics↗

bioRxiv2023

Comparative Analysis of Whole Transcriptome Single-Cell Sequencing Technologies in Complex Tissues

The development of single-cell omics tools has enabled scientists to study the tumor microenvironment (TME) in unprecedented detail. However, each of the different techniques may have its unique strengths and limitations. Here we directly compared two commercially available high-throughput single-cell RNA sequencing (scRNA-seq) technologies - droplet-based 10X Chromium vs. microwell-based BD Rhapsody - using paired samples from patients with localized prostate cancer (PCa) undergoing a radical prostatectomy. Although high technical consistency was observed in unraveling the whole transcriptome, the relative abundance of cell populations differed. Cells with low-mRNA content such as T cells were underrepresented in the droplet-based system, at least partly due to lower RNA capture rates. In contrast, microwell based scRNA-seq recovered less cells of epithelial origin. Moreover, we discovered platform-dependent variabilities in mRNA quantification and cell-type marker annotation. Overall, our study provides important information for selection of the appropriate scRNA-seq platform and for the interpretation of published results. SYNOPSISO_LIComparison of scRNA-seq protocols uncovers disparities in RNA-to-library conversion C_LIO_LIMicrowell-based scRNA-seq technology excels in capturing low-mRNA content cells C_LIO_LIBiased transcriptomes due to gene specific RNA detection efficacies by both platforms C_LIO_LIThe study guides in informed scRNA-seq platform selection and data interpretation C_LI

cancer biology↗

bioRxiv2022

High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is characterized by molecular heterogeneity with diverse immune cell infiltration patterns, which has been linked to both, therapy sensitivity and resistance. However, full understanding of how immune cell phenotypes vary across different patient and tumor subgroups is lacking. Here, we dissect the NSCLC tumor microenvironment at high resolution by integrating 1,212,463 single-cells from 538 samples and 309 patients across 29 datasets, including our own dataset capturing cells with low mRNA content. Based on the cellular composition we stratified patients into immune deserted, B cell, T cell, and myeloid cell subtypes. Using bulk samples with genomic and clinical information, we identified specific cellular components associated with tumor histology and genotypes. Analysis of cells with low mRNA content uncovered distinct subpopulations of tissue-resident neutrophils (TRNs) that acquire new functional properties in the tissue microenvironment, providing evidence for the plasticity of TRNs. TRN-derived gene signature was associated with anti-PD-L1 treatment failure in a large NSCLC cohort. In briefSalcher, Sturm, Horvath et al. integrate single-cell datasets to generate the largest transcriptome atlas in NSCLC, refining patient stratification based on tumor immune phenotypes, and revealing associations of histological subtypes and genotypes with specific cellular composition patterns. Coverage of cells with low mRNA content by single-cell sequencing identifies distinct tissue-resident neutrophil subpopulations, which acquire new properties within the tumor microenvironment. Gene signature from tissue-resident neutrophils is associated with immune checkpoint inhibitor treatment failure. The integrated atlas is publicly available online (https://luca.icbi.at), allowing the dissection of tumor-immune cell interactions in NSCLC. HighlightsO_LIHigh-resolution single-cell atlas of the tumor microenvironment (TME) in NSCLC. C_LIO_LIHistological tumor subtypes and driver genes imprint specific cellular TME patterns. C_LIO_LIscRNA-seq of cells with low transcript count identifies distinct tissue-resident neutrophil (TRN) subpopulations and non-canonical functional properties in the TME niche. C_LIO_LITRN gene signature identifies patients who are refractory to treatment with PD-L1 inhibitors. C_LI O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/491204v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@1050b6aorg.highwire.dtl.DTLVardef@3088c8org.highwire.dtl.DTLVardef@6408b8org.highwire.dtl.DTLVardef@1788c22_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗