Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors.
Nat Genet 2017 May; 49(5):708-718
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. Nat Genet 2017 May; 49(5):708-718
Li, Huipeng; Courtois, Elise T; Sengupta, Debarka; Tan, Yuliana; Chen, Kok Hao; Goh, Jolene Jie Lin; Kong, Say Li; Chua, Clarinda; Hon, Lim Kiat; Tan, Wah Siew; Wong, Mark; Choi, Paul Jongjoon; Wee, Lawrence J K; Hillmer, Axel M; Tan, Iain Beehuat; Robson, Paul; and Prabhakar, Shyam, "Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors." (2017). Faculty Research 2017. 65.