Biology subjects

Kazdal, D. N.

Publications and source records attributed to Kazdal, D. N..

3 recordsLinked to original sources

bioRxiv2023

Glycodelin acts as an immunomodulator in NSCLC and is a predictor of poor prognosis for patients receiving immunotherapy

Lung cancer has been shown to be targetable by novel immunotherapies which reactivate the immune system and enable tumor cell killing. However, treatment failure and resistance to these therapies is common. Consideration of sex as a factor influencing therapy resistance is still rare. We hypothesize that the success of the treatment is impaired by the presence of the immunosuppressive pregnancy-associated glycoprotein glycodelin that is expressed in patients with non-small-cell lung cancer (NSCLC). We demonstrate that the glycan pattern of NSCLC-derived glycodelin detected by a lectin-based enrichment assay highly resembles amniotic fluid-derived glycodelin A, which is known to have immunosuppressive properties. NSCLC-derived glycodelin interacts with immune cells in vitro and regulates the expression of genes associated with inflammatory and tumor microenvironment pathways. In tumor microarray samples of patients, high glycodelin staining in tumor areas results in an impaired overall survival of female patients. Moreover, glycodelin colocalizes to tumor infiltrating CD8+ T cells and pro-tumorigenic M2 macrophages. High serum concentrations of glycodelin prior to immunotherapy are associated with a poor progression-free survival (p < 0.001) of female patients receiving PD-(L)1 inhibitors. In summary, our findings suggest that glycodelin not only is a promising immunological biomarker for early identification of female patients that do not benefit from the costly immunotherapy, but also represents a promising immunotherapeutic target in NSCLC to improve therapeutic options in lung cancer. BackgroundImmunotherapy is one of the major achievements in the last decade of lung cancer treatment. However, resistance to treatment is common und not well understood. Glycodelin is an immunosuppressive protein well described during the establishment of a pregnancy. We investigated its influence on immune cells and patients receiving immunotherapy with a focus on the sex of the patients. Translational relevanceOur study examined that NSCLC-derived glycodelin shares similarities to amniotic fluid-derived glycodelin A and is predictive for a worse response to immunotherapy in female patients. Therefore, glycodelin might be a key player influencing a sex-specific response to immunotherapy in lung cancer.

cancer biology↗

bioRxiv2020

YAP orchestrates heterotypic endothelial cell communication via HGF/c-MET signaling in liver tumorigenesis

Next to cell autonomous mechanisms, the oncogene yes-associated protein (YAP) controls liver tumor initiation and progression via cell extrinsic functions creating a tumor-supporting environment. However, how YAP affects the microenvironment and in particular the vascular niche, which contributes to liver disease and hepatocarcinogenesis, is poorly understood. In this study, histo-morphological and molecular characterization of murine liver endothelial cells (ECs) populations and human single cell data revealed the presence of liver sinusoidal endothelial cells (LSECs) and capillary endothelial cells (CECs) in healthy liver tissue. In YAPS127A-induced tumorigenesis, a gradual replacement of LSECs by CECs was associated with dynamic changes in the expression of genes involved in EC subtype-specific paracrine communication. The formation of new potential communication hubs connecting CECs and LSECs included the hepatocyte growth factor (Hgf)/c-Met signaling pathway. In hepatocytes and tumor cells, YAP/TEA domain transcription factor 4 (TEAD4)-dependent transcriptional induction of osteopontin (Opn) stimulated c-Met expression in ECs with CEC phenotype, which sensitized these cells to the pro-migratory effects of LSEC-derived Hgf. In human HCCs, the presence of a migration-associated tip-cell signature correlated with poor clinical outcome and the loss of LSEC marker gene expression. In addition, the replacement of LSECs by CECs with exclusive c-MET expression in a CEC subpopulation was confirmed at the single cell level. In summary, YAP-dependent changes of the liver vascular niche comprise the formation of heterologous communication hubs (e.g. the HGF/c-Met axis), in which tumor cell-derived factors modify the crosstalk between LSECs and CECs.

cancer biology↗

bioRxiv2019

Automated sample preparation with SP3 for low-input clinical proteomics

High-throughput and streamlined workflows are essential in clinical proteomics for standardized processing of samples originating from a variety of sources, including fresh frozen tissue, FFPE tissue, or blood. To reach this goal, we have implemented single-pot solid-phase-enhanced sample preparation (SP3) on a liquid handling robot for automated processing (autoSP3) of tissue lysates in a 96-well format, performing unbiased protein purification and digestion, and delivering peptides that can be directly analyzed by LCMS. AutoSP3 eliminates hands-on time and minimizes the risk of error, reduces variability in protein quantification and improves longitudinal performance and reproducibility. We demonstrate the distinguishing ability of autoSP3 to process low-input samples, reproducibly quantifying 500-1000 proteins from 100-1000 cells (<100 ng protein). Furthermore, we applied this approach to a cohort of clinical FFPE pulmonary adenocarcinoma (ADC) samples, and recapitulate their separation into known histological growth patterns based on proteome profiles. Collectively, autoSP3 provides a generic, scalable, and cost-effective pipeline for routine and standardized proteomic sample processing that should enable reproducible proteomics in a broad range of clinical and non-clinical applications.

molecular biology↗