Single‐cell transcriptomic analysis reveals circadian rhythm disruption associated with poor prognosis and drug‐resistance in lung adenocarcinoma

Abstract

Circadian rhythm disruption (CRD) represents a major contributor to tumor proliferation. Nonetheless, the role of CRD in the clinical prediction of cancer outcomes has not been well studied. In this study, we developed a computational algorithm, which was implemented in an open‐source R package CRDscore, to define the intratumoral status of circadian disruption in three representative single‐cell RNA‐seq data sets of lung adenocarcinoma. We found that the malignant cells with high CRDscore were characterized by activation of glycolysis and epithelial–mesenchymal transition pathways. Furthermore, cell communication analysis indicated that CRD played a pivotal role in T cell exhaustion, which may be responsible for the poor prognosis of the malignancy. We then validated the findings with public bulk transcriptome datasets involving 22 cancer types. Cox regression analysis revealed that the CRDscore was a valuable prognostic biomarker. A model containing 23 circadian‐related genes performed well in predicting immunotherapeutic outcomes in 14 independent cohorts. Importantly, decreased CRDscore was detect by RNA sequencing on H1299 cells with melatonin treatment. Meanwhile, the cells downregulated the expression level of SNAIL and TWIST, which contributed to an invasive phenotype. In conclusion, this study provides a novel computational framework for characterizing CRD status using single‐cell transcriptomic data and further confirmed the molecular mechanisms underlying metabolic reprogramming and T cell exhaustion under CRD. The better understanding of the mechanisms may provide new possibilities for incorporating “anticancer approaches based on circadian clocks” into the treatment protocols of precision medicine.

Anterior gradient‐2 regulates cell communication by coordinating cytokine–chemokine signaling and immune infiltration in breast cancer

“…Because the interaction between malignant cells and T cells is a crucial prerequisite for effective anticancer therapy, cell communication analysis was carried out. We first annotated T cell subtypes with known cell type marker genes (Table S1), 24 and only observed seven subclusters of T cells: CD4 exhaust, CD4 native, CD4 Th17, CD4 Treg, CD8 cyto, CD8 exhaust, and CD8 native (Figure 4F,G). Cell–cell communication was evaluated using CellPhoneDB.…”

“…The cell clusters were annotated based on well‐known previously reported cellular markers (Table S1). 24 Differences in the expression of these marker genes between the groups were identified using the default nonparametric Wilcoxon rank sum test.…”

Hsa‐miR‐503‐5p regulates CTDSPL to accelerate cisplatin resistance and angiogenesis of lung adenocarcinoma cells

“…Chemotherapy drugs like cisplatin and other platinum agents have wide application in solid tumors, such as LUAD, as main anticancer agents. Nevertheless, efficacy decreased due to the emergence of drug resistance (Cao et al, 2021;He et al, 2022). More and more studies add up to the statement that miRNAs feature in cancer development and drug resistance (Hussen et al, 2023).…”

Single-Cell Sequencing Analysis Reveals the Correlation between Obesity and Circadian Rhythm in Spermatogenesis and Its Microenvironment

“…In order to explore the relationship between obesity and circadian rhythm in testicular cells, we constructed CRD_scores using a algorithm developed by He et al (29). The algorithm basically contains calculation of normalized values for bulk RNA-seq and TPM for scRNA-seq, random sampling and score calculation based on the centered gene expression matrix.…”