TGF-β in Developmental and Fibrogenic EMTs

Overview

Journal Semin Cancer Biol

Specialty Oncology

Date 2022 Oct 2

PMID 36183999

Authors

Jun Ho Lee

Joan Massague

Affiliations

Soon will be listed here.

Abstract

TGF-β plays a prominent role as an inducer of epithelial-mesenchymal transitions (EMTs) during development and wound healing and in disease conditions such as fibrosis and cancer. During these processes EMT occurs together with changes in cell proliferation, differentiation, communication, and extracellular matrix remodeling that are orchestrated by multiple signaling inputs besides TGF-β. Chief among these inputs is RAS-MAPK signaling, which is frequently required for EMT induction by TGF-β. Recent work elucidated the molecular basis for the cooperation between the TGF-β-SMAD and RAS-MAPK pathways in the induction of EMT in embryonic, adult and carcinoma epithelial cells. These studies also provided direct mechanistic links between EMT and progenitor cell differentiation during gastrulation or intra-tumoral fibrosis during cancer metastasis. These insights illuminate the nature of TGF-β driven EMTs as part of broader processes during development, fibrogenesis and metastasis.

Citing Articles

Chitosan-Artesunate nanoparticles: A dual anti-fibrotic and anti-inflammatory strategy for preventing bleb fibrosis post-glaucoma filtration surgery.

Liu J, Wang S, Tan G, Tong B, Wu Y, Zhang L Drug Deliv Transl Res. 2025; .

PMID: 40019651 DOI: 10.1007/s13346-025-01819-7.

CC-chemokine ligand 18, CXC motif chemokine 13 and osteopontin as biomarkers of silicosis and asbestosis: a prospective observational study.

Wu N, Xue C, Yu S, Wang Y, Sun D, Ye Q Sci Rep. 2025; 15(1):6819.

PMID: 40000810 PMC: 11861896. DOI: 10.1038/s41598-025-91423-z.

Exploring TGF-β Signaling in Cancer Progression: Prospects and Therapeutic Strategies.

Sheikh K, Amjad M, Irfan M, Anjum S, Majeed T, Riaz M Onco Targets Ther. 2025; 18:233-262.

PMID: 39989503 PMC: 11846535. DOI: 10.2147/OTT.S493643.

Phosphorylation of FOXN3 by NEK6 promotes pulmonary fibrosis through Smad signaling.

Yu J, Li Y, Li Y, Liu X, Huo Q, Wu N Nat Commun. 2025; 16(1):1865.

PMID: 39984467 PMC: 11845461. DOI: 10.1038/s41467-025-56922-7.

MICAL1 Mediates TGF-β1-Induced Epithelial-to-Mesenchymal Transition and Metastasis of Hepatocellular Carcinoma by Activating Smad2/3.

Zhuang X, Wang C, Ge Z, Wu M, Chen M, Chen Z Cell Biochem Biophys. 2025; .

PMID: 39954154 DOI: 10.1007/s12013-025-01668-8.

References

Aceto N, Bardia A, Miyamoto D, Donaldson M, Wittner B, Spencer J . Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014; 158(5):1110-1122. PMC: 4149753. DOI: 10.1016/j.cell.2014.07.013. View

Ben-Haim N, Lu C, Guzman-Ayala M, Pescatore L, Mesnard D, Bischofberger M . The nodal precursor acting via activin receptors induces mesoderm by maintaining a source of its convertases and BMP4. Dev Cell. 2006; 11(3):313-23. DOI: 10.1016/j.devcel.2006.07.005. View

Huang Y, Hu J, Chen F, Lecomte N, Basnet H, David C . ID1 Mediates Escape from TGFβ Tumor Suppression in Pancreatic Cancer. Cancer Discov. 2019; 10(1):142-157. PMC: 6954299. DOI: 10.1158/2159-8290.CD-19-0529. View

David C, Massague J . Contextual determinants of TGFβ action in development, immunity and cancer. Nat Rev Mol Cell Biol. 2018; 19(7):419-435. PMC: 7457231. DOI: 10.1038/s41580-018-0007-0. View

Shi Y, Hata A, Lo R, Massague J, Pavletich N . A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature. 1997; 388(6637):87-93. DOI: 10.1038/40431. View

Schafer M, Werner S . Cancer as an overhealing wound: an old hypothesis revisited. Nat Rev Mol Cell Biol. 2008; 9(8):628-38. DOI: 10.1038/nrm2455. View

Aragona M, Dekoninck S, Rulands S, Lenglez S, Mascre G, Simons B . Defining stem cell dynamics and migration during wound healing in mouse skin epidermis. Nat Commun. 2017; 8:14684. PMC: 5339881. DOI: 10.1038/ncomms14684. View

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

Oft M, Akhurst R, Balmain A . Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat Cell Biol. 2002; 4(7):487-94. DOI: 10.1038/ncb807. View

10.

Sun X, Meyers E, Lewandoski M, Martin G . Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Genes Dev. 1999; 13(14):1834-46. PMC: 316887. DOI: 10.1101/gad.13.14.1834. View

11.

Vincent T, Neve E, Johnson J, Kukalev A, Rojo F, Albanell J . A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-beta mediated epithelial-mesenchymal transition. Nat Cell Biol. 2009; 11(8):943-50. PMC: 3769970. DOI: 10.1038/ncb1905. View

12.

Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J . The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000; 2(2):84-9. DOI: 10.1038/35000034. View

13.

Xi Q, Wang Z, Zaromytidou A, Zhang X, Chow-Tsang L, Liu J . A poised chromatin platform for TGF-β access to master regulators. Cell. 2011; 147(7):1511-24. PMC: 3582033. DOI: 10.1016/j.cell.2011.11.032. View

14.

Ramadoss S, Chen X, Wang C . Histone demethylase KDM6B promotes epithelial-mesenchymal transition. J Biol Chem. 2012; 287(53):44508-17. PMC: 3531764. DOI: 10.1074/jbc.M112.424903. View

15.

Lamouille S, Connolly E, Smyth J, Akhurst R, Derynck R . TGF-β-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. J Cell Sci. 2012; 125(Pt 5):1259-73. PMC: 3324583. DOI: 10.1242/jcs.095299. View

16.

Lin T, Ponn A, Hu X, Law B, Lu J . Requirement of the histone demethylase LSD1 in Snai1-mediated transcriptional repression during epithelial-mesenchymal transition. Oncogene. 2010; 29(35):4896-904. PMC: 3093107. DOI: 10.1038/onc.2010.234. View

17.

Katsuno Y, Derynck R . Epithelial plasticity, epithelial-mesenchymal transition, and the TGF-β family. Dev Cell. 2021; 56(6):726-746. DOI: 10.1016/j.devcel.2021.02.028. View

18.

Morgani S, Su J, Nichols J, Massague J, Hadjantonakis A . The transcription factor Rreb1 regulates epithelial architecture, invasiveness, and vasculogenesis in early mouse embryos. Elife. 2021; 10. PMC: 8131102. DOI: 10.7554/eLife.64811. View

19.

Haensel D, Jin S, Sun P, Cinco R, Dragan M, Nguyen Q . Defining Epidermal Basal Cell States during Skin Homeostasis and Wound Healing Using Single-Cell Transcriptomics. Cell Rep. 2020; 30(11):3932-3947.e6. PMC: 7218802. DOI: 10.1016/j.celrep.2020.02.091. View

20.

Ray S, Li H, Metzger E, Schule R, Leiter A . CtBP and associated LSD1 are required for transcriptional activation by NeuroD1 in gastrointestinal endocrine cells. Mol Cell Biol. 2014; 34(12):2308-17. PMC: 4054299. DOI: 10.1128/MCB.01600-13. View