Biology subjects

Mertz, K. D.

Publications and source records attributed to Mertz, K. D..

5 recordsLinked to original sources

bioRxiv2025

SAUNA - Simulated Annealing for Unique Nucleosome Arrangements from Cell-Free DNA-Sequencing Data

WithdrawalThis preprint has been withdrawn by the authors. While the preprint cites the work by Schoepflin et al. (2013) (reference [20] in the preprint), it has been brought to the authors attention that the preprint may not appropriately acknowledge the extent to which their work depends on the work by Schoepflin et al. (2013). The authors apologize for this oversight and want to emphasize that they did not intend to misattribute the work of Schoepflin et al. (2013) and want to thank them for the code of NucPosSimulator which is a core component of SAUNAs algorithm. Therefore, the authors do not wish this work to be cited as reference for the project. For any questions, please contact the corresponding author.

bioinformatics↗

bioRxiv2024

ECM-free patient-derived organoids preserve diverse prostate cancer lineages and uncover in vitro-enriched cell types

Patient-derived organoids (PDOs) offer new opportunities to model various cancers. However, their application in prostate cancer (PCa) has been hampered by poor success rates and overgrowth of cell types which are not representative of the patient samples. By exploiting a cohort of 164 PCa patient samples and tuning several culture parameters, we show that an extracellular matrix-free (ECM)-free culture system increases the take-rate of PDOs with luminal-like and PCa features. Single-cell RNA sequencing (scRNA-seq) reveals that ECM-free PDOs comprise cell populations associated with known PCa signatures and exhibit transcriptomic resemblance with their respective parental tumors. In addition, we define organoid-associated cell type signatures and identify markers discriminating tumors versus benign cells ex vivo and in situ. Furthermore, we generate the first prostate PDO single-cell atlas integrating previously-published scRNA-seq datasets and our newly- generated data. We show that Matrigel-based organoid cultures derived from primary PCa are essentially composed of benign-like epithelial cells, irrespective of the dataset or the malignant nature of the tissue of origin. In contrast, ECM-free conditions maintain heterogenous patient-specific luminal tumor cell populations and enrich in intermediate cell types. Ultimately, our work will significantly enhance the potential of PDOs in basic and translational PCa research.

cancer biology↗

bioRxiv2024

Mapping the niche of breast cancer metastases in lung and liver

Breast cancer progression to visceral organs such as lung and liver is regarded as a dreadful event, unequivocally associated with a poor prognosis. Yet, these vital sites are characterized by highly diverse cellular microenvironments and physiological functions, suggesting that they may influence cancer cells behavior in divergent ways. Unexpectedly, we find that while the liver microenvironment fosters metastasis-promoting properties and boosts secondary spread, the lungs impose a roadblock to the same processes. Using patient data and tissues from rapid autopsy, as well as mouse models with barcode-mediated metastasis tracing, niche labeling technology and single cell analysis of both tumor cells and their direct microenvironment, we dissect cellular and molecular microenvironmental factors that impose this differential behavior. Among these, we identify BMP2-producing endothelial cells as critical players within the liver metastatic niche, capable to enhance metastasis-to-metastasis dissemination. Targeting BMP2 receptor on breast cancer cells suppresses their metastasis-forming ability. Altogether, we reveal a contrast in the site-specific behavior of lung and liver metastases in breast cancer, highlighting microenvironmental factors that contribute to this diversity, as well as organ-specific opportunities for intervention.

cancer biology↗

bioRxiv2024

Cell-autonomous and non-cell-autonomous effects of arginase-II on cardiac aging

Aging is a predominant risk factor for heart disease. Aging heart reveals low-grade chronic inflammation, cell apoptosis, cardiac fibrosis, and increased vulnerability to ischemic injury. The underlying molecular mechanisms responsible for the cardiac aging phenotype and its susceptibility to injury are far from being fully understood. Although previous literature reports a role of the mitochondrial enzyme arginase-II (Arg-II) in development of heart failure, contradictory results are reported and no systematic analysis of cellular expression and localization of Arg-II in the heart has been performed. Whether and how Arg-II participates in cardiac aging are still unknown. In this study, we demonstrate, to our surprise, that Arg-II is not expressed in cardiomyocytes from aged mice and human patients, but upregulated in non-myocytes of the aging heart, including macrophages, fibroblasts, endothelial cells. Mice with genetic deficiency of arg-ii (arg-ii-/-) are protected from age-associated cardiac inflammation, myocyte apoptosis, interstitial and perivascular fibrosis, endothelial-mesenchymal transition (EndMT), and susceptibility to ischemic injury. Further experiments show that Arg-II mediates IL-1{beta} release from macrophages of old mice, contributing to the above-described cardiac aging phenotype. In addition, Arg-II enhances mitochondrial reactive oxygen species (mtROS) and activates cardiac fibroblasts that is inhibited by inhibition of mtROS. Thus, our study demonstrates a non-cell-autonomous effect of Arg-II on cardiomyocytes, fibroblasts, and endothelial cells mediated by IL-1{beta} from aging macrophages as well as a cell-autonomous effect of Arg-II through mtROS in fibroblasts contributing to cardiac aging phenotype.

physiology↗

bioRxiv2018

B cells sustain inflammation and improve survival in human melanoma

Tumor associated inflammation is one of important predictors of response to immune checkpoint blockade. Understanding molecular processes that regulate tumor inflammation is key to improve the efficacy of checkpoint blockade. Established mechanisms that underlie therapy response and resistance have centered on anti-tumor T cell responses.\n\nWe show that tumor-associated B cells are vital to T cell functions. They promote recruitment of CD8+ T cells through plasmablast-like cells with expression of pro- and anti-inflammatory factors. Plasmablast-like cells are associated with improved survival of patients with metastatic melanoma and their response to checkpoint blockade. Plasmablast-like B cells express chemokines for T cell-attraction. Depletion of tumor-associated B cells by anti-CD20 immunotherapy of metastatic melanoma patients causes a remarkable decrease in tumor CD8+ T cells. These findings indicate that tumor-associated B cells orchestrate and sustain tumor inflammation, recruit CD8+ T effector cells and are key to therapeutic response and patients overall survival.

cancer biology↗