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Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors.

Huipeng LiElise T CourtoisDebarka SenguptaYuliana TanKok Hao ChenJolene Jie Lin GohSay Li KongClarinda ChuaLim Kiat HonWah Siew TanMark WongPaul Jongjoon ChoiLawrence J K WeeAxel Maximilian HillmerIain Beehuat TanPaul RobsonShyam Prabhakar
Published in: Nature genetics (2017)
Intratumoral heterogeneity is a major obstacle to cancer treatment and a significant confounding factor in bulk-tumor profiling. We performed an unbiased analysis of transcriptional heterogeneity in colorectal tumors and their microenvironments using single-cell RNA-seq from 11 primary colorectal tumors and matched normal mucosa. To robustly cluster single-cell transcriptomes, we developed reference component analysis (RCA), an algorithm that substantially improves clustering accuracy. Using RCA, we identified two distinct subtypes of cancer-associated fibroblasts (CAFs). Additionally, epithelial-mesenchymal transition (EMT)-related genes were found to be upregulated only in the CAF subpopulation of tumor samples. Notably, colorectal tumors previously assigned to a single subtype on the basis of bulk transcriptomics could be divided into subgroups with divergent survival probability by using single-cell signatures, thus underscoring the prognostic value of our approach. Overall, our results demonstrate that unbiased single-cell RNA-seq profiling of tumor and matched normal samples provides a unique opportunity to characterize aberrant cell states within a tumor.
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