Analysis of snRNA-seq from CDX Models of Non-Small Cell Lung Cancer Identified Subpopulation of Cells Potentially Responsible for Tumor Progression

Circulating tumor cells (CTCs) are considered as seeds of metastasis and have potential to be used as biomarkers in cancer.  Understanding the biology of CTCs is critical to evaluate tumor progression and response to treatment. Additionally, studying transcriptome of CTCs–derived tumors aids in deciphering the causes underlying metastasis. Single nuclei-RNA-sequencing (snRNA-seq) is an emerging technology that allows investigators to study individual cells with molecular typing to that drives tumor growth and resistance to therapy. In this study, we use novel human CTC-derived xenograft (CDX) mouse models of non-small cell lung cancer (NSCLC) and snRNA-seq to determine genetic and cellular drivers of metastasis development in this deadly disease.

Proteomics analysis of patient-derived xenograft (PDX) and CDX tumor samples revealed that the chemorefractory and more aggressive sample contained significantly more ribosomal proteins than the chemoresponsive one. Analysing snRNA-seq of the same samples, we discovered subpopulations of cells that express ribosomal protein coding genes on high levels. Interestingly, the expression levels and numbers of those genes were higher for metastatic models of NSCLC. As a result of cell type annotation, we found that cell subgroups with high content of ribosomal protein coding gene expression can be identified as ciliated epithelial cells. Based on multiomics analysis of PDX and CDX tumors, we developed a hypothesis that subsets of cells with high levels of ribosomal protein coding genes may be used as markers of metastasis development. We validated our findings using previously published scRNA-seq data for lung adenocarcinoma. 

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