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 Clevers; Michael F. Clarke; Stephen R. Quake

doi:10.1038/nbt.2038

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

Research output: Contribution to journal › Article › peer-review

570 Scopus citations

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 language	English
Pages (from-to)	1120-1127
Number of pages	8
Journal	Nature Biotechnology
Volume	29
Issue number	12
DOIs	https://doi.org/10.1038/nbt.2038
State	Published - 13 Nov 2011
Externally published	Yes

Bibliographical note

Funding 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.

Funding

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.

Funders	Funder number
Ludwig Foundation
Machiah Foundation	K99-CA151673
National Institutes of Health	P01-CA139490
U.S. Department of Defense	W81XWH-10-1-0500
National Cancer Institute	U54CA126524
California Institute for Regenerative Medicine
Harvard Stem Cell Institute

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nbt.2038

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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

@article{496a27ccdf3c406394dd1756f90dd8d0,

title = "Single-cell dissection of transcriptional heterogeneity in human colon tumors",

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.",

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

note = "Funding 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{\textquoteright}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.",

year = "2011",

month = nov,

day = "13",

doi = "10.1038/nbt.2038",

language = "אנגלית",

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Dalerba, P, Kalisky, T, Sahoo, D, Rajendran, PS, Rothenberg, ME, Leyrat, AA, Sim, S, Okamoto, J, Johnston, DM, Qian, D, Zabala, M, Bueno, J, Neff, NF, Wang, J, Shelton, AA, Visser, B, Hisamori, S, Shimono, Y, Van De Wetering, M, Clevers, H, Clarke, MF & Quake, SR 2011, 'Single-cell dissection of transcriptional heterogeneity in human colon tumors', Nature Biotechnology, vol. 29, no. 12, pp. 1120-1127. https://doi.org/10.1038/nbt.2038

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T1 - Single-cell dissection of transcriptional heterogeneity in human colon tumors

AU - Dalerba, Piero

AU - Kalisky, Tomer

AU - Sahoo, Debashis

AU - Rajendran, Pradeep S.

AU - Rothenberg, Michael E.

AU - Leyrat, Anne A.

AU - Sim, Sopheak

AU - Okamoto, Jennifer

AU - Johnston, Darius M.

AU - Qian, Dalong

AU - Zabala, Maider

AU - Bueno, Janet

AU - Neff, Norma F.

AU - Wang, Jianbin

AU - Shelton, Andrew A.

AU - Visser, Brendan

AU - Hisamori, Shigeo

AU - Shimono, Yohei

AU - Van De Wetering, Marc

AU - Clevers, Hans

AU - Clarke, Michael F.

AU - Quake, Stephen R.

N1 - Funding 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.

PY - 2011/11/13

Y1 - 2011/11/13

N2 - 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.

AB - 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.

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Single-cell dissection of transcriptional heterogeneity in human colon tumors

Abstract

Bibliographical note

Funding

UN SDGs

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