Single-cell dissection of transcriptional heterogeneity in human colon tumors

Piero Dalerba, Tomer Kalisky, Debashis Sahoo, Pradeep S. Rajendran, Michael E. Rothenberg, Anne A. Leyrat, Sopheak Sim, Jennifer Okamoto, Darius M. Johnston, Dalong Qian, Maider Zabala, Janet Bueno, Norma F. Neff, Jianbin Wang, Andrew A. Shelton, Brendan Visser, Shigeo Hisamori, Yohei Shimono, Marc Van De Wetering, Hans CleversMichael F. Clarke, Stephen R. Quake

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432 Citations (Scopus)

Abstract

Cancer is often viewed as a caricature of normal developmental processes, but the extent to which its cellular heterogeneity truly recapitulates multilineage differentiation processes of normal tissues remains unknown. Here we implement single-cell PCR gene-expression analysis to dissect the cellular composition of primary human normal colon and colon cancer epithelia. We show that human colon cancer tissues contain distinct cell populations whose transcriptional identities mirror those of the different cellular lineages of normal colon. By creating monoclonal tumor xenografts from injection of a single (n = 1) cell, we demonstrate that the transcriptional diversity of cancer tissues is largely explained by in vivo multilineage differentiation and not only by clonal genetic heterogeneity. Finally, we show that the different gene-expression programs linked to multilineage differentiation are strongly associated with patient survival. We develop two-gene classifier systems (KRT20 versus CA1, MS4A12, CD177, SLC26A3) that predict clinical outcomes with hazard ratios superior to those of pathological grade and comparable to those of microarray-derived multigene expression signatures.

Original languageEnglish
Pages (from-to)1120-1127
Number of pages8
JournalNature Biotechnology
Volume29
Issue number12
DOIs
Publication statusPublished - 01-12-2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

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  • Cite this

    Dalerba, P., Kalisky, T., Sahoo, D., Rajendran, P. S., Rothenberg, M. E., Leyrat, A. A., Sim, S., Okamoto, J., Johnston, D. M., Qian, D., Zabala, M., Bueno, J., Neff, N. F., Wang, J., Shelton, A. A., Visser, B., Hisamori, S., Shimono, Y., Van De Wetering, M., ... Quake, S. R. (2011). Single-cell dissection of transcriptional heterogeneity in human colon tumors. Nature Biotechnology, 29(12), 1120-1127. https://doi.org/10.1038/nbt.2038