Cell-Type-Specific Profibrotic Scores across Multi-Organ Systems Predict Cancer Prognosis.

Huihui Fan,Zhongming Zhao,Peilin Jia

doi:10.3390/cancers13236024

Abstract

Simple SummaryFibrosis is a major player and contributor in the tumor microenvironment. Profibrotic changes precede the early development and establishment of a variety of human diseases, such as fibrosis and cancer. Being able to measure such early signals at the single cell level is critically useful for identifying new mechanisms and potential drug targets for a wide range of diseases. This study was designed to computationally identify profibrotic cell populations using single-cell transcriptomic data and to identify gene signatures that could predict cancer prognosis.Fibrosis is a major cause of mortality. Key profibrotic mechanisms are common pathways involved in tumorigenesis. Characterizing the profibrotic phenotype will help reveal the underlying mechanisms of early development and progression of a variety of human diseases, such as fibrosis and cancer. Fibroblasts have been center stage in response to various stimuli, such as viral infections. However, a comprehensive catalog of cell types involved in this process is currently lacking. Here, we deployed single-cell transcriptomic data across multi-organ systems (i.e., heart, kidney, liver, and lung) to identify novel profibrotic cell populations based on ECM pathway activity at single-cell resolution. In addition to fibroblasts, we also reported that epithelial, endothelial, myeloid, natural killer T, and secretory cells, as well as proximal convoluted tubule cells of the nephron, were significantly actively involved. Cell-type-specific gene signatures were enriched in viral infection pathways, enhanced glycolysis, and carcinogenesis, among others; they were validated using independent datasets in this study. By projecting the signatures into bulk TCGA tumor samples, we could predict prognosis in the patients using profibrotic scores. Our profibrotic cellular phenotype is useful for identifying new mechanisms and potential drug targets at the cell-type level for a wide range of diseases involved in ECM pathway activation.

Highlights

Fibrogenic responses can be triggered by disease-related injury in any organ
By leveraging large-scale, single-cell transcriptomic data across multiple organs simultaneously from patients who succumbed to SARS-CoV-2 viral infection, we computationally defined cells that exhibit profibrotic phenotype as those that are significantly active in expressing extracellular matrix (ECM) genes
In addition to fibroblast cells, we identified six previously under-recognized cell types involved in this process

Summary

Introduction

Fibrogenic responses can be triggered by disease-related injury in any organ. When injury progresses over a prolonged period, inevitable scarring occurs; it causes cellular dysfunction and organ failure [1]. A plethora of diseases in different organ systems are associated with fibrotic changes These include, but are not limited to, the commonly reported the tissue of the lung [6], liver [7], kidney [8], and heart [9]. Thanks to the massive production of high-resolution single-cell transcriptomic sequencing data (scRNA-seq), especially during the COVID-19 pandemic, more granular mechanism studies in fibrosis, down to the cell-type level, are gaining power. These data are critically useful in revealing the complex cell network that underpins fibrosis in multiple organ systems [16,17,18]. In addition to fibroblasts and resident myofibroblasts, a diversity of cell types, such as epithelial and mesenchymal cells in the lung [19] and endothelial and tubular cells in the kidney [20], have been reported to contribute to pathologic fibrosis

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