Biology subjects

Reichel, K.

Publications and source records attributed to Reichel, K..

4 recordsLinked to original sources

bioRxiv2024

Shift in cellular crosstalk reveals the immunosuppressive environment in cholangiocarcinoma patients.

Background and aimsCholangiocarcinoma (CCA) is a deadly disease, and this cancer entity is characterized by an abundant stroma. The tumor microenvironment (TME) plays an important role in aggressive behavior and poor response to therapeutics; however, underlying pathways are unknown. MethodsTo fill this gap, we used multiplexed immunohistochemistry, high-dimensional phenotyping, and transcriptomics to analyze human CCA samples and identify cell cluster crosstalk in patients with a poor prognosis. ResultsOur findings confirmed the presence of Tregs and the lack of effector memory cells in the tumor. New findings are the spatiality of the effector memory cells being more present in the peripheral tissue, for some reason these immune cells fail to reach the tumor niche. We revealed cancer crosstalk with macrophages and stromal cells and identified responsible genes in the poor prognosis group. Amongst the responsible ligand pairs are GAS6-AXL belonging to the TAM family. We then identified VCAN-TLR2 to be present and influencing the ECM in a way to supports immune exhaustion. Last, EGFR-TGF-{beta} is expressed in macrophages and this finding is important in Tregs induction and blocking cytotoxic T cell function. ConclusionsThe multiple mechanisms leading to the exclusion of relevant immune cells needed for an anti-cancer response and mechanisms leading to active immune suppression are part of complex cell-cell crosstalk. This study provides a deeper insight into the immune exhausted phenotype in CCA.

cancer biology↗

bioRxiv2023

TIGIT drives the immunosuppressive environment by downregulation of metalloproteinases MMP2 and MMP14 in perihilar cholangiocarcinoma.

BackgroundCheckpoint blockade in cholangiocarcinoma (CCA) is promising; however, little is known about the response to treatment in CCA subtypes. In this study, we investigated the spatial immune environment in combination with checkpoint expression in perihilar CCA (pCCA). Materials & MethodsThe levels of checkpoint molecules (PD-1, PD-L1, PD-L2, LAG-3, ICOS, TIGIT, TIM-3, and CTLA-4), macrophages (CD68), and T cells (CD4 and CD8) were assessed by multiplex immunofluorescence (mIF) in 50 patients. We investigated the transcriptomic profile using the NanoString Cancer Progression Panel, and validation was performed by mIF on tissue sections from 24 patients. ResultsThe expression of checkpoint molecules TIGIT, CTLA-4, and LAG-3 alone and in combination with other checkpoint molecules was more abundant in the Central Tumor (CT) and Invasive Margin (IM) than in peritumoral tissue (PT) (CD4 and CD8 TIGIT p<0.0001 for both CD4 and CD8 CTLA-4, p<0.0001 and p < 0.001, respectively, and CD8 LAG-3 p < 0.05). MMP2 and MMP14 were differentially expressed in patients with high TIGIT expression. ConclusionThe immune environment in pCCA is characterized by the expression of multiple checkpoints, demonstrating the complexity of ICI treatment. High TIGIT expression drives an immunosuppressive environment by modulating the extracellular matrix. Future clinical trials in pCCA could consider TIGIT as a therapeutically relevant target for (combination) treatment.

cancer biology↗

bioRxiv2021

Software choice and depth of sequence coverage can impact plastid genome assembly - A case study in the narrow endemic Calligonum bakuense

Most plastid genome sequences are assembled from short-read whole-genome sequencing data, yet the impact that sequence coverage and the choice of assembly software can have on the accuracy of the resulting assemblies is poorly understood. In this study, we test the impact of both factors on plastid genome assembly in the threatened and rare endemic shrub Calligonum bakuense, which forms a distinct lineage in the genus Calligonum. We aim to characterize the differences across plastid genome assemblies generated by different assembly software tools and levels of sequence coverage and to determine if these differences are large enough to affect the phylogenetic position inferred for C. bakuense. Four assembly software tools (FastPlast, GetOrganelle, IOGA, and NOVOPlasty) and three levels of sequence coverage (original depth, 2,000x, and 500x) are compared in our analyses. The resulting assemblies are evaluated with regard to reproducibility, contig number, gene complement, inverted repeat length, and computation time; the impact of sequence differences on phylogenetic tree inference is also assessed. Our results show that software choice can have a considerable impact on the accuracy and reproducibility of plastid genome assembly and that GetOrganelle produced the most consistent assemblies for C. bakuense. Moreover, we found that a cap in sequence coverage can reduce both the sequence variability across assembly contigs and computation time. While no evidence was found that the sequence variability across assemblies was large enough to affect the phylogenetic position inferred for C. bakuense, differences among the assemblies may influence genotype recognition at the population level.

plant biology↗

bioRxiv2019

Structural basis for functional interactions in dimers of SLC26 transporters

The SLC26 family of transporters maintains anion equilibria in all kingdoms of life. The family shares a 7 + 7 transmembrane segments inverted repeat architecture with the SLC4 and SLC23 families, but holds a regulatory STAS domain in addition. While the only experimental SLC26 structure is monomeric, SLC26 proteins form structural and functional dimers in the lipid membrane. Here we resolve the structure of an SLC26 dimer embedded in a lipid membrane and characterize its functional relevance by combining PELDOR distance measurements and biochemical studies with MD simulations and spin-label ensemble refinement. Our structural model reveals a unique interface different from the SLC4 and SLC23 families. The functionally relevant STAS domain exerts a stabilizing effect on regions central in this dimer. Characterization of heterodimers indicates that protomers in the dimer functionally interact. The combined structural and functional data define the framework for a mechanistic understanding of functional cooperativity in SLC26 dimers.

biochemistry↗