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DeNardo, D.

Publications and source records attributed to DeNardo, D..

2 recordsLinked to original sources

SC2MeNetDrug: A computational tool to uncover inter-cell signaling targets and identify relevant drugs based on single cell RNA-seq data

Single-cell RNA sequencing (scRNA-seq) is a powerful technology to investigate the transcriptional programs in stromal, immune, and disease cells, like tumor cells or neurons within the Alzheimers Disease (AD) brain or tumor microenvironment (ME) or niche. Cell-cell communications within ME play important roles in disease progression and immunotherapy response and are novel and critical therapeutic targets. Though many tools of scRNA-seq analysis have been developed to investigate the heterogeneity and sub-populations of cells, few were designed for uncovering cell-cell communications of ME and predicting the potentially effective drugs to inhibit the communications. Moreover, the data analysis processes of discovering signaling communication networks and effective drugs using scRNA-seq data are complex and involve a set of critical analysis processes and external supportive data resources, which are difficult for researchers who have no strong computational background and training in scRNA-seq data analysis. To address these challenges, in this study, we developed a novel open-source computational tool, sc2MeNetDrug (https://fuhaililab.github.io/sc2MeNetDrug/). It was specifically designed using scRNA-seq data to identify cell types within disease MEs, uncover the dysfunctional signaling pathways within individual cell types and interactions among different cell types, and predict effective drugs that can potentially disrupt cell-cell signaling communications. sc2MeNetDrug provided a user-friendly graphical user interface to encapsulate the data analysis modules, which can facilitate the scRNA-seq data-based discovery of novel inter-cell signaling communications and novel therapeutic regimens.

bioinformatics↗

Stromal architecture directs early dissemination in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) is an extremely metastatic and lethal disease. Here in both murine and human PDA we demonstrate that extracellular matrix architecture regulates cell extrusion and subsequent invasion from intact ductal structures through Tumor-Associated Collagen Signatures (TACS), resulting in early dissemination from histologically pre-malignant lesions and continual invasion from well-differentiated disease. Furthermore, we show that pancreatitis results in invasion-conducive architectures, thus priming the stroma prior to malignant disease. Analysis in novel microfluidics-derived microtissues and in vivo demonstrates decreased extrusion and invasion following focal adhesion kinase (FAK) inhibition, consistent with decreased metastasis. Thus, data suggest that targeting FAK or strategies to re-engineer and normalize tumor microenvironments, may have a role not only in also in very early disease but also for limiting continued dissemination from unresectable disease. Likewise, it may be beneficial to employ stroma targeting strategies to resolve precursor diseases such as pancreatitis in order to remove stromal architectures that increase risk for early dissemination. Impact StatementCollagen architectures in the tumor stroma facilitate dissemination of carcinoma cells from the earliest histologically "pre-malignant" lesions and continue to promote disease spread from well-differentiated PDA.

cancer biology↗