Cited by 1,080Single-cell and spatial transcriptomicsGene expression and cancer classificationCancer Genomics and Diagnostics

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

Li, Huipeng, Courtois, Elise T, Sengupta, Debarka, Tan, Yuliana, Chen, Kok Hao, Goh, Jolene Jie Lin, Kong, Say Li, Chua, Clarinda +9 more·2017·Nature Genetics

Abstract

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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Crossref · 10.1038/ng.3818

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Authors
Li, H., Courtois, E. T., Sengupta, D., Tan, Y., Chen, K. H., Goh, J. J. L., Kong, S. L., Chua, C., Hon, L. K., Tan, W. S., Wong, M., Choi, P. J., Wee, L. J. K., Hillmer, A. M., Tan, I. B., Robson, P., & Prabhakar, S.
Affiliations
  • Genome Institute of Singapore (SG)
  • Indraprastha Institute of Information Technology Delhi (IN)
  • National Cancer Centre Singapore (SG)
  • Singapore General Hospital (SG)
  • Institute for Infocomm Research (SG)
  • Duke-NUS Medical School (SG)
  • University of Connecticut (US)
Corresponding author
  • Tan, Iain Beehuat
  • Robson, Paul
  • Prabhakar, Shyam
Venue
Nature Genetics
Published
2017-03-20
Volume
49
Issue
5
Pages
708-718
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
OpenAlex
W2600453489
Cited by
1,080
References
55
Citations by year
2026: 50 · 2025: 86 · 2024: 128 · 2023: 146 · 2022: 152 · 2021: 163 · 2020: 154 · 2019: 102 · 2018: 75 · 2017: 20 · 2014: 1
FWCI
39.30
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
colorectal cancer, intratumoral heterogeneity, cancer-associated fibroblasts, tumor microenvironment, epithelial-mesenchymal transition, single-cell transcriptomics, tumor subtypes
MeSH terms
A549 Cells, Algorithms, Cell Line, Fibroblasts, Humans, Immunohistochemistry, Prognosis, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Cluster Analysis, Survival Analysis, In Situ Hybridization, Fluorescence, Sequence Analysis, RNA, Genetic Heterogeneity, K562 Cells, Gene Expression Profiling, Principal Component Analysis, Cell Line, Tumor, Epithelial-Mesenchymal Transition, Single-Cell Analysis, Transcriptome

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