Single-cell RNA Sequencing Reveals Kidney Cancer Cellular Origins

Single-cell RNA Sequencing Reveals Kidney Cancer Cellular Origins
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Renal cell carcinomas (RCCs) are heterogeneous cancers encompassing several histologically and molecularly diverse tumor groups. Thought to arise from kidney tubular epithelial cells, clear cell RCC (ccRCC) is the most common type. A new study using single cell RNA sequencing (scRNA-seq) revealed the cellular origins for more than 10 RCC subtypes, each with distinct pathways.

The study from the University of Michigan Rogel Cancer Center involved an analysis of the RNA of individual cells within samples from both renal carcinoma tumor samples and benign adjacent kidney tissues (14 samples from nine patients).  “Identification of cellular orthologs in the benign tissues that share transcriptional signatures with the tumor epithelia of specific RCC subtypes may indicate a putative cell of origin,” the authors write. The study was published in PNAS.

Among the cell types comprising the tumor immune microenvironment the researchers did not find a large representation of lymphoid cells in the ccRCC cohort; instead, a large number of myeloid populations were detected. The team found showed marked enrichment specifically in the average macrophage-B population in tumor (37%) compared with benign kidney (1%), while monocytes exhibited an opposite trend, with enrichment in benign tissues.

“Single cell RNA sequencing was key to allowing us to monitor gene expression patterns in each individual cell, revealing the mechanisms at play within the tumor microenvironment that can predict overall survival,” says study author Arul Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at Michigan Medicine.” By understanding the cell type where a cancer originates, it may allow us to target more precise treatments for that cancer type as well as better understand response to therapy.”

The researchers discovered an active role for tumor epithelia in promoting immune cell infiltration, potentially explaining why ccRCC responds to immune checkpoint inhibitors, despite having a low neoantigen burden. “A dichotomy in tumor microenvironment phenotype exists, whereby patients with higher endothelial cell content in primary disease tend to have better overall survival, but metastatic ccRCC patients with high endothelial cell content respond poorly to immunotherapy,” the authors write. “Conversely, individuals with a higher tumor immune fraction had poorer overall survival in the localized setting but benefited more from immunotherapeutic intervention for metastatic ccRCC.”

The authors conclude that the lack of immunotherapy response and endothelial cell fraction has important clinical implications. “The current study, therefore, significantly contributes toward understanding disease ontogenies and the molecular dynamics of tumor epithelia and the microenvironment.”