TWIST1-induced miR-424 reversibly drives mesenchymal programming while inhibiting tumor initiation

David J. Drasin, Anna L. Guarnieri, Deepika Neelakantan, Jihye Kim, Joshua H. Cabrera, Chu An Wang, Vadym Zaberezhnyy, Pierluigi Gasparini, Luciano Cascione, Kay Huebner, Aik-Choon Tan, Heide L. Ford

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Epithelial-to-mesenchymal transition (EMT) is a dynamic process that relies on cellular plasticity. Recently, the process of an oncogenic EMT, followed by a reverse mesenchymal-to-epithelial transition (MET), has been implicated as critical in the metastatic colonization of carcinomas. Unlike governance of epithelial programming, regulation of mesenchymal programming is not well understood in EMT. Here, we describe and characterize the first microRNA that enhances exclusively mesenchymal programming. We demonstrate that miR-424 is upregulated early during a TWIST1 or SNAI1-induced EMT, and that it causes cells to express mesenchymal genes without affecting epithelial genes, resulting in a mixed/intermediate EMT. Furthermore, miR-424 increases motility, decreases adhesion, and induces a growth arrest, changes associated with a complete EMT that can be reversed when miR-424 expression is lowered, concomitant with an MET-like process. Breast cancer patient miR-424 levels positively associate with TWIST1/2 and EMT-like gene signatures, and miR-424 is increased in primary tumors versus matched normal breast. However, miR-424 is downregulated in patient metastases versus matched primary tumors. Correspondingly, miR-424 decreases tumor initiation and is posttranscriptionally downregulated in macrometastases in mice, suggesting the need for biphasic expression of miR-424 to transit the EMT-MET axis. Next-generation RNA sequencing revealed miR-424 regulates numerous EMT and cancer stemness-associated genes, including TGFBR3, whose downregulation promotes mesenchymal phenotypes, but not tumor-initiating phenotypes. Instead, we demonstrate that increased MAPK-ERK signaling is critical for miR-424-mediated decreases in tumor-initiating phenotypes. These findings suggest miR-424 plays distinct roles in tumor progression, potentially facilitating earlier, but repressing later, stages of metastasis by regulating an EMT-MET axis.

Original languageEnglish
Pages (from-to)1908-1921
Number of pages14
JournalCancer Research
Volume75
Issue number9
DOIs
Publication statusPublished - 2015 May 1
Externally publishedYes

Fingerprint

Epithelial-Mesenchymal Transition
Neoplasms
Down-Regulation
Phenotype
Genes
Neoplasm Metastasis
RNA Sequence Analysis
MicroRNAs

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Drasin, D. J., Guarnieri, A. L., Neelakantan, D., Kim, J., Cabrera, J. H., Wang, C. A., ... Ford, H. L. (2015). TWIST1-induced miR-424 reversibly drives mesenchymal programming while inhibiting tumor initiation. Cancer Research, 75(9), 1908-1921. https://doi.org/10.1158/0008-5472.CAN-14-2394

TWIST1-induced miR-424 reversibly drives mesenchymal programming while inhibiting tumor initiation. / Drasin, David J.; Guarnieri, Anna L.; Neelakantan, Deepika; Kim, Jihye; Cabrera, Joshua H.; Wang, Chu An; Zaberezhnyy, Vadym; Gasparini, Pierluigi; Cascione, Luciano; Huebner, Kay; Tan, Aik-Choon; Ford, Heide L.

In: Cancer Research, Vol. 75, No. 9, 01.05.2015, p. 1908-1921.

Research output: Contribution to journalArticle

Drasin, DJ, Guarnieri, AL, Neelakantan, D, Kim, J, Cabrera, JH, Wang, CA, Zaberezhnyy, V, Gasparini, P, Cascione, L, Huebner, K, Tan, A-C & Ford, HL 2015, 'TWIST1-induced miR-424 reversibly drives mesenchymal programming while inhibiting tumor initiation', Cancer Research, vol. 75, no. 9, pp. 1908-1921. https://doi.org/10.1158/0008-5472.CAN-14-2394
Drasin DJ, Guarnieri AL, Neelakantan D, Kim J, Cabrera JH, Wang CA et al. TWIST1-induced miR-424 reversibly drives mesenchymal programming while inhibiting tumor initiation. Cancer Research. 2015 May 1;75(9):1908-1921. https://doi.org/10.1158/0008-5472.CAN-14-2394
Drasin, David J. ; Guarnieri, Anna L. ; Neelakantan, Deepika ; Kim, Jihye ; Cabrera, Joshua H. ; Wang, Chu An ; Zaberezhnyy, Vadym ; Gasparini, Pierluigi ; Cascione, Luciano ; Huebner, Kay ; Tan, Aik-Choon ; Ford, Heide L. / TWIST1-induced miR-424 reversibly drives mesenchymal programming while inhibiting tumor initiation. In: Cancer Research. 2015 ; Vol. 75, No. 9. pp. 1908-1921.
@article{4f9aaa6208ac4c32a77c7cf726253ad1,
title = "TWIST1-induced miR-424 reversibly drives mesenchymal programming while inhibiting tumor initiation",
abstract = "Epithelial-to-mesenchymal transition (EMT) is a dynamic process that relies on cellular plasticity. Recently, the process of an oncogenic EMT, followed by a reverse mesenchymal-to-epithelial transition (MET), has been implicated as critical in the metastatic colonization of carcinomas. Unlike governance of epithelial programming, regulation of mesenchymal programming is not well understood in EMT. Here, we describe and characterize the first microRNA that enhances exclusively mesenchymal programming. We demonstrate that miR-424 is upregulated early during a TWIST1 or SNAI1-induced EMT, and that it causes cells to express mesenchymal genes without affecting epithelial genes, resulting in a mixed/intermediate EMT. Furthermore, miR-424 increases motility, decreases adhesion, and induces a growth arrest, changes associated with a complete EMT that can be reversed when miR-424 expression is lowered, concomitant with an MET-like process. Breast cancer patient miR-424 levels positively associate with TWIST1/2 and EMT-like gene signatures, and miR-424 is increased in primary tumors versus matched normal breast. However, miR-424 is downregulated in patient metastases versus matched primary tumors. Correspondingly, miR-424 decreases tumor initiation and is posttranscriptionally downregulated in macrometastases in mice, suggesting the need for biphasic expression of miR-424 to transit the EMT-MET axis. Next-generation RNA sequencing revealed miR-424 regulates numerous EMT and cancer stemness-associated genes, including TGFBR3, whose downregulation promotes mesenchymal phenotypes, but not tumor-initiating phenotypes. Instead, we demonstrate that increased MAPK-ERK signaling is critical for miR-424-mediated decreases in tumor-initiating phenotypes. These findings suggest miR-424 plays distinct roles in tumor progression, potentially facilitating earlier, but repressing later, stages of metastasis by regulating an EMT-MET axis.",
author = "Drasin, {David J.} and Guarnieri, {Anna L.} and Deepika Neelakantan and Jihye Kim and Cabrera, {Joshua H.} and Wang, {Chu An} and Vadym Zaberezhnyy and Pierluigi Gasparini and Luciano Cascione and Kay Huebner and Aik-Choon Tan and Ford, {Heide L.}",
year = "2015",
month = "5",
day = "1",
doi = "10.1158/0008-5472.CAN-14-2394",
language = "English",
volume = "75",
pages = "1908--1921",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - TWIST1-induced miR-424 reversibly drives mesenchymal programming while inhibiting tumor initiation

AU - Drasin, David J.

AU - Guarnieri, Anna L.

AU - Neelakantan, Deepika

AU - Kim, Jihye

AU - Cabrera, Joshua H.

AU - Wang, Chu An

AU - Zaberezhnyy, Vadym

AU - Gasparini, Pierluigi

AU - Cascione, Luciano

AU - Huebner, Kay

AU - Tan, Aik-Choon

AU - Ford, Heide L.

PY - 2015/5/1

Y1 - 2015/5/1

N2 - Epithelial-to-mesenchymal transition (EMT) is a dynamic process that relies on cellular plasticity. Recently, the process of an oncogenic EMT, followed by a reverse mesenchymal-to-epithelial transition (MET), has been implicated as critical in the metastatic colonization of carcinomas. Unlike governance of epithelial programming, regulation of mesenchymal programming is not well understood in EMT. Here, we describe and characterize the first microRNA that enhances exclusively mesenchymal programming. We demonstrate that miR-424 is upregulated early during a TWIST1 or SNAI1-induced EMT, and that it causes cells to express mesenchymal genes without affecting epithelial genes, resulting in a mixed/intermediate EMT. Furthermore, miR-424 increases motility, decreases adhesion, and induces a growth arrest, changes associated with a complete EMT that can be reversed when miR-424 expression is lowered, concomitant with an MET-like process. Breast cancer patient miR-424 levels positively associate with TWIST1/2 and EMT-like gene signatures, and miR-424 is increased in primary tumors versus matched normal breast. However, miR-424 is downregulated in patient metastases versus matched primary tumors. Correspondingly, miR-424 decreases tumor initiation and is posttranscriptionally downregulated in macrometastases in mice, suggesting the need for biphasic expression of miR-424 to transit the EMT-MET axis. Next-generation RNA sequencing revealed miR-424 regulates numerous EMT and cancer stemness-associated genes, including TGFBR3, whose downregulation promotes mesenchymal phenotypes, but not tumor-initiating phenotypes. Instead, we demonstrate that increased MAPK-ERK signaling is critical for miR-424-mediated decreases in tumor-initiating phenotypes. These findings suggest miR-424 plays distinct roles in tumor progression, potentially facilitating earlier, but repressing later, stages of metastasis by regulating an EMT-MET axis.

AB - Epithelial-to-mesenchymal transition (EMT) is a dynamic process that relies on cellular plasticity. Recently, the process of an oncogenic EMT, followed by a reverse mesenchymal-to-epithelial transition (MET), has been implicated as critical in the metastatic colonization of carcinomas. Unlike governance of epithelial programming, regulation of mesenchymal programming is not well understood in EMT. Here, we describe and characterize the first microRNA that enhances exclusively mesenchymal programming. We demonstrate that miR-424 is upregulated early during a TWIST1 or SNAI1-induced EMT, and that it causes cells to express mesenchymal genes without affecting epithelial genes, resulting in a mixed/intermediate EMT. Furthermore, miR-424 increases motility, decreases adhesion, and induces a growth arrest, changes associated with a complete EMT that can be reversed when miR-424 expression is lowered, concomitant with an MET-like process. Breast cancer patient miR-424 levels positively associate with TWIST1/2 and EMT-like gene signatures, and miR-424 is increased in primary tumors versus matched normal breast. However, miR-424 is downregulated in patient metastases versus matched primary tumors. Correspondingly, miR-424 decreases tumor initiation and is posttranscriptionally downregulated in macrometastases in mice, suggesting the need for biphasic expression of miR-424 to transit the EMT-MET axis. Next-generation RNA sequencing revealed miR-424 regulates numerous EMT and cancer stemness-associated genes, including TGFBR3, whose downregulation promotes mesenchymal phenotypes, but not tumor-initiating phenotypes. Instead, we demonstrate that increased MAPK-ERK signaling is critical for miR-424-mediated decreases in tumor-initiating phenotypes. These findings suggest miR-424 plays distinct roles in tumor progression, potentially facilitating earlier, but repressing later, stages of metastasis by regulating an EMT-MET axis.

UR - http://www.scopus.com/inward/record.url?scp=84936852732&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84936852732&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-14-2394

DO - 10.1158/0008-5472.CAN-14-2394

M3 - Article

VL - 75

SP - 1908

EP - 1921

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 9

ER -