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.
Bibliographical noteFunding Information:
This study was supported by National Institutes of Health (NIH) grants U54-CA126524 and P01-CA139490 (to S.R.Q. and M.F.C.), the NIH Director’s Pioneer Awards (to S.R.Q.) and a grant from the Ludwig foundation (to M.F.C.). P.D. was supported by a training grant from the California Institute for Regenerative Medicine (CIRM) and by a BD Biosciences Stem Cell Research Grant (Summer 2011). T.K. was supported by a fellowship from the Machiah Foundation. D.S. was supported by NIH grant K99-CA151673, by Department of Defense grant W81XWH-10-1-0500 and a grant from the Siebel Stem Cell Institute and the Thomas and Stacey Siebel Foundation. We wish to thank R. Tibshirani, D. Witten, L. Warren, R.A. White III, E. Gilbert, P. Lovelace, M. Palmor, C. Donkers and S.P. Miranda for helpful discussion and technical support in many moments during the completion of this study.