Biology subjects

Hartmann, K.

Publications and source records attributed to Hartmann, K..

4 recordsLinked to original sources

bioRxiv2023

T cells in testicular germ cell tumors: new evidence of fundamental contributions by rare subsets

BACKGROUNDImmune cell infiltration is heterogeneous but common in testicular germ cell tumors (TGCT) and pre-invasive germ cell neoplasia in situ (GCNIS). Tumor-infiltrating T cells including regulatory T (Treg) and follicular helper T (Tfh) cells are found in other cancer entities, but their contributions to TGCT are unknown. METHODSHuman testis specimens from independent patient cohorts were analyzed using immunohistochemistry, flow cytometry and single-cell RNA sequencing (scRNA-seq) with special emphasis on delineating T cell subtypes. RESULTSProfound changes in immune cell composition within TGCT, shifting from macrophages in normal testes to T cells plus B and dendritic cells in TGCT, were documented. In most samples (96%), the CD4+ T cell frequency exceeded that of CD8+ cells, with decreasing numbers from central to peripheral tumor areas, and to tumor-free, contralateral testes. T cells including Treg and Tfh were most abundant in seminoma compared to mixed tumors and embryonal carcinoma. CONCLUSIONDespite considerable heterogeneity between patients, T cell subtypes form a key part of the TGCT microenvironment. The novel finding of rare Treg and Tfh cells in human testis suggests their involvement in TGCT pathobiology, with implications for understanding tumor progression, to assess patients prognosis, and as putative targets for personalized immunotherapy.

cancer biology↗

bioRxiv2020

Interpreting coronary artery disease GWAS results: A functional genomics approach assessing biological significance

Genome-wide association studies (GWAS) have implicated 58 loci in coronary artery disease (CAD). However, the biological basis for these associations, the relevant genes, and causative variants often remain uncertain. Since the vast majority of GWAS loci reside outside coding regions, most exert regulatory functions. Here we explore the complexity of each of these loci, using tissue specific RNA sequencing data from GTEx to identify genes that exhibit altered expression patterns in the context of GWAS-significant loci, expanding the list of candidate genes from the 75 currently annotated by GWAS to 245, with almost half of these transcripts being non-coding. Tissue specific allelic expression imbalance data, also from GTEx, allows us to uncover GWAS variants that mark functional variation in a locus, e.g., rs7528419 residing in the SORT1 locus, in liver specifically, and rs72689147 in the GUYC1A1 locus, across a variety of tissues. We consider the GWAS variant rs1412444 in the LIPA locus in more detail as an example, probing tissue and transcript specific effects of genetic variation in the region. By evaluating linkage disequilibrium (LD) between tissue specific eQTLs, we reveal evidence for multiple functional variants within loci. We identify 3 variants (rs1412444, rs1051338, rs2250781) that when considered together, each improve the ability to account for LIPA gene expression, suggesting multiple interacting factors. These results refine the assignment of 58 GWAS loci to likely causative variants in a handful of cases and for the remainder help to re-prioritize associated genes and RNA isoforms, suggesting that ncRNAs maybe a relevant transcript in almost half of CAD GWAS results. Our findings support a multifactorial system where a single variant can influence multiple genes and each genes is regulated by multiple variants.

genomics↗

bioRxiv2019

Exponential Growth of Glioblastoma In Vivo Driven by Rapidly Dividing and Outwardly Migrating Cancer Stem Cells

How overall tumor growth emerges from the properties of functionally heterogeneous tumor cell subpopulations is a fundamental question of cancer biology. Here we combined lineage tracing, continuous monitoring of tumor mass, proliferation assays and transcriptomics with mathematical modeling and statistical inference to dissect the growth of glioblastoma in mice. We found that tumors grow exponentially at the rate of symmetric divisions of brain tumor stem cells (BTSCs). Spatial modeling predicts, and data show, that BTSCs accumulate at the tumor rim rather than in the core. The physiological differentiation hierarchy downstream of BTSCs is preserved in mice and humans: transit amplifying progenitors give rise to terminally differentiated cells. Consistent with our quantification of the mechanisms underlying tumor growth, molecular data show elevated expression of cell cycle-and migration-related genes in BTSCs. Our systematic approach reveals fundamental properties of glioblastoma and may be transferable to the study of other animal models of cancer.

cancer biology↗

bioRxiv2017

Autonomous Combinatorial Color Barcoding For Multiplexing Single Molecule RNA Visualization

Single molecular fluorescence in situ hybridization (smFISH) detects RNA transcripts with spatial information and digital molecular counting. However, the broad usage of smFISH is still hindered by the complex chemical probe conjugation or microscopy set-up, especially for investigating multiple gene expression. Here we present a multiple fluorophore enzymatic labeling method (termed HuluFISH) for smFISH probes to achieve flexible combinatorial color barcoding in single hybridization step. The multiplex capacity of HuluFISH follows an exponential growth with the increase of the number of fluorophore types. We demonstrate that this method can be used to detect cellular heterogeneity in embryonic mouse brain on single cell level.

molecular biology↗