Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer

Abstract

Lung cancer is a highly heterogeneous disease. Cancer cells and cells within the tumor microenvironment together determine disease progression, as well as response to or escape from treatment. To map the cell type-specific transcriptome landscape of cancer cells and their tumor microenvironment in advanced non-small cell lung cancer (NSCLC), we analyze 42 tissue biopsy samples from stage III/IV NSCLC patients by single cell RNA sequencing and present the large scale, single cell resolution profiles of advanced NSCLCs. In addition to cell types described in previous single cell studies of early stage lung cancer, we are able to identify rare cell types in tumors such as follicular dendritic cells and T helper 17 cells. Tumors from different patients display large heterogeneity in cellular composition, chromosomal structure, developmental trajectory, intercellular signaling network and phenotype dominance. Our study also reveals a correlation of tumor heterogeneity with tumor associated neutrophils, which might help to shed light on their function in NSCLC.

Tobacco Smoke and Electronic Cigarette Vapor Alter Enhancer RNA Expression That Can Regulate the Pathogenesis of Lung Squamous Cell Carcinoma

“…Our results also indicated that two eRNAs are negatively correlated with increased expression of tumor stromal cells (p-value < 0.05) (Figure 2). Stromal cells promote tumor growth by releasing cytokines and growth factors, and the receptors for these ligands are commonly found in cancer cells [29,30]. Advanced-stage tumors often undergo a multitude of interactions with tumor stromal cells and immune cells.…”

Lung-Resident Mesenchymal Stem Cell Fates within Lung Cancer

“…As the most originating sites of the different lung cancer types were correlated with the areas of distinct epithelial cells and their progenitor cells, even LR-MSCs could hypothetically lead to de-differentiation of lung stem cells, thereby initiating lung cancer; or at least differentiate into (divers) non-tumorigenic stromal cells that ultimately define the histological type of NSCLC [ 12 , 16 , 33 ]. Conformingly, MSC-related marker expressions (e.g., CD90, CD44, CD105, CD73 as well as LR-MSC specific HOX transcription factors) were associated with low pathologic stage in NSCLC and/or accounted for a reduced overall survival of respective patients [ 47 , 48 , 49 , 50 ].…”

“…Accordingly, high expression levels of ACTA2 (commonly known as alpha-smooth muscle actin or α-SMA), a frequently used marker for myofibroblasts/ CAFs were further associated with poor survival periods in NSCLC [ 66 , 67 ]. Thus, lung CAFs contribute to the malignant signature for advanced stage lung cancer [ 12 ].…”

“…Activated fibroblasts (myofibroblasts and cancer-associated fibroblasts, CAF) and associated extracellular matrix, mesenchymal cells and vascular cells as well as infiltrating immune cells are central stromal cells, which define inter- and intratumoral heterogeneity. Lung SCC, for example, exhibit a higher intratumoral heterogeneity than lung AD whereas lung AD was found to have a higher metastatic rate than lung SCC [ 11 , 12 ]. Stroma-enriched tumors in NSCLC patients, in particular, usually have a worse prognosis and were associated with reduced disease-free periods compared to stroma-poor tumors [ 13 ].…”

“…Stroma-enriched tumors in NSCLC patients, in particular, usually have a worse prognosis and were associated with reduced disease-free periods compared to stroma-poor tumors [ 13 ]. Especially for advanced NSCLC, a more precise profiling of individual patients on stroma-cellular levels beyond the traditional pathological definitions would be highly desirable, because the identification of decisive tumor stroma cells with their respective origin, their relevant marker genes, and their specified intratumor cell–cell interactions could potentially serve as biomarkers and targets for individual therapeutic decisions for lung cancer patients at advanced stages [ 12 ].…”