A microRNA miR-34a-regulated bimodal switch targets notch in colon cancer stem cells

Pengcheng Bu; Kai Yuan Chen; Joyce Huan Chen; Lihua Wang; Jewell Walters; Yong Jun Shin; Julian P. Goerger; Jian Sun; Mavee Witherspoon; Nikolai Rakhilin; Jiahe Li; Herman Yang; Jeff Milsom; Sang Lee; Warren Zipfel; Moonsoo M. Jin; Zeynep H. Gümüş; Steven M. Lipkin; Xiling Shen

doi:10.1016/j.stem.2013.03.002

A microRNA miR-34a-regulated bimodal switch targets notch in colon cancer stem cells

Pengcheng Bu, Kai Yuan Chen, Joyce Huan Chen, Lihua Wang, Jewell Walters, Yong Jun Shin, Julian P. Goerger, Jian Sun, Mavee Witherspoon, Nikolai Rakhilin, Jiahe Li, Herman Yang, Jeff Milsom, Sang Lee, Warren Zipfel, Moonsoo M. Jin, Zeynep H. Gümüş, Steven M. Lipkin, Xiling Shen

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

322 Scopus citations

Abstract

microRNAs regulate developmental cell-fate decisions, tissue homeostasis, and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell-fate determinant in early-stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR-34a distributes at high levels in differentiating progeny, whereas low levels of miR-34a demarcate self-renewing CCSCs. Moreover, miR-34a loss of function and gain of function alter the balance between self-renewal versus differentiation both in vitro and in vivo. Mechanistically, miR-34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal and differentiation. In contrast, the canonical cell-fate determinant Numb regulates Notch levels in a continuously graded manner. Altogether, our findings highlight a unique microRNA-regulated mechanism that converts noisy input into a toggle switch for robust cell-fate decisions in CCSCs.

Original language	English
Pages (from-to)	602-615
Number of pages	14
Journal	Cell Stem Cell
Volume	12
Issue number	5
DOIs	https://doi.org/10.1016/j.stem.2013.03.002
State	Published - 2 May 2013
Externally published	Yes

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Bu, P., Chen, K. Y., Chen, J. H., Wang, L., Walters, J., Shin, Y. J., Goerger, J. P., Sun, J., Witherspoon, M., Rakhilin, N., Li, J., Yang, H., Milsom, J., Lee, S., Zipfel, W., Jin, M. M., Gümüş, Z. H., Lipkin, S. M., & Shen, X. (2013). A microRNA miR-34a-regulated bimodal switch targets notch in colon cancer stem cells. Cell Stem Cell, 12(5), 602-615. https://doi.org/10.1016/j.stem.2013.03.002

@article{a21ae9398a0d4ceaa9a9bc9316bd014e,

title = "A microRNA miR-34a-regulated bimodal switch targets notch in colon cancer stem cells",

abstract = "microRNAs regulate developmental cell-fate decisions, tissue homeostasis, and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell-fate determinant in early-stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR-34a distributes at high levels in differentiating progeny, whereas low levels of miR-34a demarcate self-renewing CCSCs. Moreover, miR-34a loss of function and gain of function alter the balance between self-renewal versus differentiation both in vitro and in vivo. Mechanistically, miR-34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal and differentiation. In contrast, the canonical cell-fate determinant Numb regulates Notch levels in a continuously graded manner. Altogether, our findings highlight a unique microRNA-regulated mechanism that converts noisy input into a toggle switch for robust cell-fate decisions in CCSCs.",

author = "Pengcheng Bu and Chen, {Kai Yuan} and Chen, {Joyce Huan} and Lihua Wang and Jewell Walters and Shin, {Yong Jun} and Goerger, {Julian P.} and Jian Sun and Mavee Witherspoon and Nikolai Rakhilin and Jiahe Li and Herman Yang and Jeff Milsom and Sang Lee and Warren Zipfel and Jin, {Moonsoo M.} and G{\"u}m{\"u}{\c s}, {Zeynep H.} and Lipkin, {Steven M.} and Xiling Shen",

note = "Funding Information: We thank Michael Elowitz and members of the Shen, Lipkin, Elowitz, and Jin laboratories for discussions and advice. We also thank Harley McAdams, Kenneth Kemphues, Tudorita Tumbar, and Robert Weiss for their comments on the manuscript. This work was supported by grants NIGMS R01GM95990, NSF 1137269, DARPA 19-1091726, NCI R21CA162483, and NCI R21CA153049 as well as the Cornell Nanobiotechnology Center, the Cornell Stem Cell Program, and a generous gift from Matthew Bell. ",

year = "2013",

month = may,

day = "2",

doi = "10.1016/j.stem.2013.03.002",

language = "English",

volume = "12",

pages = "602--615",

journal = "Cell Stem Cell",

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Bu, P, Chen, KY, Chen, JH, Wang, L, Walters, J, Shin, YJ, Goerger, JP, Sun, J, Witherspoon, M, Rakhilin, N, Li, J, Yang, H, Milsom, J, Lee, S, Zipfel, W, Jin, MM, Gümüş, ZH, Lipkin, SM & Shen, X 2013, 'A microRNA miR-34a-regulated bimodal switch targets notch in colon cancer stem cells', Cell Stem Cell, vol. 12, no. 5, pp. 602-615. https://doi.org/10.1016/j.stem.2013.03.002

TY - JOUR

T1 - A microRNA miR-34a-regulated bimodal switch targets notch in colon cancer stem cells

AU - Bu, Pengcheng

AU - Chen, Kai Yuan

AU - Chen, Joyce Huan

AU - Wang, Lihua

AU - Walters, Jewell

AU - Shin, Yong Jun

AU - Goerger, Julian P.

AU - Sun, Jian

AU - Witherspoon, Mavee

AU - Rakhilin, Nikolai

AU - Li, Jiahe

AU - Yang, Herman

AU - Milsom, Jeff

AU - Lee, Sang

AU - Zipfel, Warren

AU - Jin, Moonsoo M.

AU - Gümüş, Zeynep H.

AU - Lipkin, Steven M.

AU - Shen, Xiling

N1 - Funding Information: We thank Michael Elowitz and members of the Shen, Lipkin, Elowitz, and Jin laboratories for discussions and advice. We also thank Harley McAdams, Kenneth Kemphues, Tudorita Tumbar, and Robert Weiss for their comments on the manuscript. This work was supported by grants NIGMS R01GM95990, NSF 1137269, DARPA 19-1091726, NCI R21CA162483, and NCI R21CA153049 as well as the Cornell Nanobiotechnology Center, the Cornell Stem Cell Program, and a generous gift from Matthew Bell.

PY - 2013/5/2

Y1 - 2013/5/2

N2 - microRNAs regulate developmental cell-fate decisions, tissue homeostasis, and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell-fate determinant in early-stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR-34a distributes at high levels in differentiating progeny, whereas low levels of miR-34a demarcate self-renewing CCSCs. Moreover, miR-34a loss of function and gain of function alter the balance between self-renewal versus differentiation both in vitro and in vivo. Mechanistically, miR-34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal and differentiation. In contrast, the canonical cell-fate determinant Numb regulates Notch levels in a continuously graded manner. Altogether, our findings highlight a unique microRNA-regulated mechanism that converts noisy input into a toggle switch for robust cell-fate decisions in CCSCs.

AB - microRNAs regulate developmental cell-fate decisions, tissue homeostasis, and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell-fate determinant in early-stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR-34a distributes at high levels in differentiating progeny, whereas low levels of miR-34a demarcate self-renewing CCSCs. Moreover, miR-34a loss of function and gain of function alter the balance between self-renewal versus differentiation both in vitro and in vivo. Mechanistically, miR-34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal and differentiation. In contrast, the canonical cell-fate determinant Numb regulates Notch levels in a continuously graded manner. Altogether, our findings highlight a unique microRNA-regulated mechanism that converts noisy input into a toggle switch for robust cell-fate decisions in CCSCs.

UR - http://www.scopus.com/inward/record.url?scp=84877263242&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2013.03.002

DO - 10.1016/j.stem.2013.03.002

M3 - Article

C2 - 23642368

AN - SCOPUS:84877263242

SN - 1934-5909

VL - 12

SP - 602

EP - 615

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 5

ER -

A microRNA miR-34a-regulated bimodal switch targets notch in colon cancer stem cells

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