A Gene Regulatory Network to Control EMT Programs in Development and Disease

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Nov 13

PMID 31712603

Citations 58

Authors

Hassan Fazilaty

Luciano Rago

Khalil Kass Youssef

Oscar H Ocana

Francisco Garcia-Asencio

Aida Arcas

Juan Galceran

M Angela Nieto

Affiliations

Soon will be listed here.

Abstract

The Epithelial to Mesenchymal Transition (EMT) regulates cell plasticity during embryonic development and in disease. It is dynamically orchestrated by transcription factors (EMT-TFs), including Snail, Zeb, Twist and Prrx, all activated by TGF-β among other signals. Here we find that Snail1 and Prrx1, which respectively associate with gain or loss of stem-like properties and with bad or good prognosis in cancer patients, are expressed in complementary patterns during vertebrate development and in cancer. We show that this complementarity is established through a feedback loop in which Snail1 directly represses Prrx1, and Prrx1, through direct activation of the miR-15 family, attenuates the expression of Snail1. We also describe how this gene regulatory network can establish a hierarchical temporal expression of Snail1 and Prrx1 during EMT and validate its existence in vitro and in vivo, providing a mechanism to switch and select different EMT programs with important implications in development and disease.

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References

Buitrago-Delgado E, Nordin K, Rao A, Geary L, Labonne C . NEURODEVELOPMENT. Shared regulatory programs suggest retention of blastula-stage potential in neural crest cells. Science. 2015; 348(6241):1332-5. PMC: 4652794. DOI: 10.1126/science.aaa3655. View

Iglesias J, Beloqui I, Garcia-Garcia F, Leis O, Vazquez-Martin A, Eguiara A . Mammosphere formation in breast carcinoma cell lines depends upon expression of E-cadherin. PLoS One. 2013; 8(10):e77281. PMC: 3790762. DOI: 10.1371/journal.pone.0077281. View

Acloque H, Ocana O, Matheu A, Rizzoti K, Wise C, Lovell-Badge R . Reciprocal repression between Sox3 and snail transcription factors defines embryonic territories at gastrulation. Dev Cell. 2011; 21(3):546-58. PMC: 3256632. DOI: 10.1016/j.devcel.2011.07.005. View

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

Blick T, Widodo E, Hugo H, Waltham M, Lenburg M, Neve R . Epithelial mesenchymal transition traits in human breast cancer cell lines. Clin Exp Metastasis. 2008; 25(6):629-42. DOI: 10.1007/s10585-008-9170-6. View

Lu W, Kang Y . Epithelial-Mesenchymal Plasticity in Cancer Progression and Metastasis. Dev Cell. 2019; 49(3):361-374. PMC: 6506183. DOI: 10.1016/j.devcel.2019.04.010. View

Lanczky A, Nagy A, Bottai G, Munkacsy G, Szabo A, Santarpia L . miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients. Breast Cancer Res Treat. 2016; 160(3):439-446. DOI: 10.1007/s10549-016-4013-7. View

Del Barrio M, Nieto M . Relative expression of Slug, RhoB, and HNK-1 in the cranial neural crest of the early chicken embryo. Dev Dyn. 2003; 229(1):136-9. DOI: 10.1002/dvdy.10456. View

Liu Q, Fu H, Sun F, Zhang H, Tie Y, Zhu J . miR-16 family induces cell cycle arrest by regulating multiple cell cycle genes. Nucleic Acids Res. 2008; 36(16):5391-404. PMC: 2532718. DOI: 10.1093/nar/gkn522. View

10.

Puram S, Tirosh I, Parikh A, Patel A, Yizhak K, Gillespie S . Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer. Cell. 2017; 171(7):1611-1624.e24. PMC: 5878932. DOI: 10.1016/j.cell.2017.10.044. View

11.

Beerling E, Seinstra D, de Wit E, Kester L, van der Velden D, Maynard C . Plasticity between Epithelial and Mesenchymal States Unlinks EMT from Metastasis-Enhancing Stem Cell Capacity. Cell Rep. 2016; 14(10):2281-8. PMC: 4802222. DOI: 10.1016/j.celrep.2016.02.034. View

12.

Smyth G . Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2006; 3:Article3. DOI: 10.2202/1544-6115.1027. View

13.

Denkert C, Liedtke C, Tutt A, von Minckwitz G . Molecular alterations in triple-negative breast cancer-the road to new treatment strategies. Lancet. 2016; 389(10087):2430-2442. DOI: 10.1016/S0140-6736(16)32454-0. View

14.

Kim J, Lee S, Li L, Park H, Park J, Lee K . High cleavage efficiency of a 2A peptide derived from porcine teschovirus-1 in human cell lines, zebrafish and mice. PLoS One. 2011; 6(4):e18556. PMC: 3084703. DOI: 10.1371/journal.pone.0018556. View

15.

Ocana O, Corcoles R, Fabra A, Moreno-Bueno G, Acloque H, Vega S . Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell. 2012; 22(6):709-24. DOI: 10.1016/j.ccr.2012.10.012. View

16.

Mani S, Guo W, Liao M, Eaton E, Ayyanan A, Zhou A . The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008; 133(4):704-15. PMC: 2728032. DOI: 10.1016/j.cell.2008.03.027. View

17.

Xie Z, Hu S, Blackshaw S, Zhu H, Qian J . hPDI: a database of experimental human protein-DNA interactions. Bioinformatics. 2009; 26(2):287-9. PMC: 2804296. DOI: 10.1093/bioinformatics/btp631. View

18.

Hamburger V, HAMILTON H . A series of normal stages in the development of the chick embryo. J Morphol. 2014; 88(1):49-92. View

19.

Lu M, Cheng H, Kern M, Potter S, Tran B, Diekwisch T . prx-1 functions cooperatively with another paired-related homeobox gene, prx-2, to maintain cell fates within the craniofacial mesenchyme. Development. 1999; 126(3):495-504. DOI: 10.1242/dev.126.3.495. View

20.

Vega S, Morales A, Ocana O, Valdes F, Fabregat I, Nieto M . Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 2004; 18(10):1131-43. PMC: 415638. DOI: 10.1101/gad.294104. View