OVOL Guides the Epithelial-hybrid-mesenchymal Transition

Overview

Journal Oncotarget

Specialty Oncology

Date 2015 May 7

PMID 25944618

Citations 69

Authors

Dongya Jia

Mohit Kumar Jolly

Marcelo Boareto

Princy Parsana

Steven M Mooney

Kenneth J Pienta

Herbert Levine

Eshel Ben-Jacob

Affiliations

Soon will be listed here.

Abstract

Metastasis involves multiple cycles of Epithelial-to-Mesenchymal Transition (EMT) and its reverse-MET. Cells can also undergo partial transitions to attain a hybrid epithelial/mesenchymal (E/M) phenotype that has maximum cellular plasticity and allows migration of Circulating Tumor Cells (CTCs) as a cluster. Hence, deciphering the molecular players helping to maintain the hybrid E/M phenotype may inform anti-metastasis strategies. Here, we devised a mechanism-based mathematical model to couple the transcription factor OVOL with the core EMT regulatory network miR-200/ZEB that acts as a three-way switch between the E, E/M and M phenotypes. We show that OVOL can modulate cellular plasticity in multiple ways - restricting EMT, driving MET, expanding the existence of the hybrid E/M phenotype and turning both EMT and MET into two-step processes. Our theoretical framework explains the differences between the observed effects of OVOL in breast and prostate cancer, and provides a platform for investigating additional signals during metastasis.

Citing Articles

IgA nephropathy.

Stamellou E, Seikrit C, Tang S, Boor P, Tesar V, Floege J Nat Rev Dis Primers. 2023; 9(1):67.

PMID: 38036542 DOI: 10.1038/s41572-023-00476-9.

Dual role of CASP8AP2/FLASH in regulating epithelial-to-mesenchymal transition plasticity (EMP).

Catalanotto M, Vaz J, Abshire C, Youngblood R, Chu M, Levine H Transl Oncol. 2023; 39:101837.

PMID: 37984255 PMC: 10689956. DOI: 10.1016/j.tranon.2023.101837.

Tumor-mediated immunosuppression and cytokine spreading affects the relation between EMT and PD-L1 status.

Lems C, Burger G, Beltman J Front Immunol. 2023; 14:1219669.

PMID: 37638024 PMC: 10449452. DOI: 10.3389/fimmu.2023.1219669.

Theoretical and computational tools to model multistable gene regulatory networks.

Bocci F, Jia D, Nie Q, Jolly M, Onuchic J Rep Prog Phys. 2023; 86(10).

PMID: 37531952 PMC: 10521208. DOI: 10.1088/1361-6633/acec88.

ZHX2 deficiency enriches hybrid MET cells through regulating E-cadherin expression.

He Y, Zhang Q, Chen Y, Wu Y, Quan Y, Chen W Cell Death Dis. 2023; 14(7):444.

PMID: 37460540 PMC: 10352340. DOI: 10.1038/s41419-023-05974-y.

References

Chao Y, Wu Q, Acquafondata M, Dhir R, Wells A . Partial mesenchymal to epithelial reverting transition in breast and prostate cancer metastases. Cancer Microenviron. 2011; 5(1):19-28. PMC: 3343195. DOI: 10.1007/s12307-011-0085-4. View

Lin K, Baritaki S, Militello L, Malaponte G, Bevelacqua Y, Bonavida B . The Role of B-RAF Mutations in Melanoma and the Induction of EMT via Dysregulation of the NF-κB/Snail/RKIP/PTEN Circuit. Genes Cancer. 2010; 1(5):409-420. PMC: 2933925. DOI: 10.1177/1947601910373795. View

Watanabe K, Villarreal-Ponce A, Sun P, Salmans M, Fallahi M, Andersen B . Mammary morphogenesis and regeneration require the inhibition of EMT at terminal end buds by Ovol2 transcriptional repressor. Dev Cell. 2014; 29(1):59-74. PMC: 4062651. DOI: 10.1016/j.devcel.2014.03.006. View

Roca H, Hernandez J, Weidner S, McEachin R, Fuller D, Sud S . Transcription factors OVOL1 and OVOL2 induce the mesenchymal to epithelial transition in human cancer. PLoS One. 2013; 8(10):e76773. PMC: 3790720. DOI: 10.1371/journal.pone.0076773. View

Chng Z, Teo A, Pedersen R, Vallier L . SIP1 mediates cell-fate decisions between neuroectoderm and mesendoderm in human pluripotent stem cells. Cell Stem Cell. 2010; 6(1):59-70. DOI: 10.1016/j.stem.2009.11.015. View

Lu M, Jolly M, Gomoto R, Huang B, Onuchic J, Ben-Jacob E . Tristability in cancer-associated microRNA-TF chimera toggle switch. J Phys Chem B. 2013; 117(42):13164-74. DOI: 10.1021/jp403156m. View

Vincent Jordan N, Johnson G, Abell A . Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer. Cell Cycle. 2011; 10(17):2865-73. PMC: 3218599. DOI: 10.4161/cc.10.17.17188. View

Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S . A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 2008; 9(6):582-9. PMC: 2396950. DOI: 10.1038/embor.2008.74. View

Schliekelman M, Taguchi A, Zhu J, Dai X, Rodriguez J, Celiktas M . Molecular portraits of epithelial, mesenchymal, and hybrid States in lung adenocarcinoma and their relevance to survival. Cancer Res. 2015; 75(9):1789-800. PMC: 4846295. DOI: 10.1158/0008-5472.CAN-14-2535. View

10.

Bracken C, Gregory P, Kolesnikoff N, Bert A, Wang J, Shannon M . A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 2008; 68(19):7846-54. DOI: 10.1158/0008-5472.CAN-08-1942. View

11.

Sampson V, David J, Puig I, Patil P, Garcia de Herreros A, Thomas G . Wilms' tumor protein induces an epithelial-mesenchymal hybrid differentiation state in clear cell renal cell carcinoma. PLoS One. 2014; 9(7):e102041. PMC: 4099076. DOI: 10.1371/journal.pone.0102041. View

12.

Boareto M, Jolly M, Lu M, Onuchic J, Clementi C, Ben-Jacob E . Jagged-Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype. Proc Natl Acad Sci U S A. 2015; 112(5):E402-9. PMC: 4321269. DOI: 10.1073/pnas.1416287112. View

13.

Thiery J, Acloque H, Huang R, Nieto M . Epithelial-mesenchymal transitions in development and disease. Cell. 2009; 139(5):871-90. DOI: 10.1016/j.cell.2009.11.007. View

14.

Lee J, Dedhar S, Kalluri R, Thompson E . The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006; 172(7):973-81. PMC: 2063755. DOI: 10.1083/jcb.200601018. View

15.

Garcia de Herreros A . Epithelial to mesenchymal transition in tumor cells as consequence of phenotypic instability. Front Cell Dev Biol. 2015; 2:71. PMC: 4264508. DOI: 10.3389/fcell.2014.00071. View

16.

Huang B, Lu M, Jolly M, Tsarfaty I, Onuchic J, Ben-Jacob E . The three-way switch operation of Rac1/RhoA GTPase-based circuit controlling amoeboid-hybrid-mesenchymal transition. Sci Rep. 2014; 4:6449. PMC: 4171704. DOI: 10.1038/srep06449. View

17.

Leroy P, Mostov K . Slug is required for cell survival during partial epithelial-mesenchymal transition of HGF-induced tubulogenesis. Mol Biol Cell. 2007; 18(5):1943-52. PMC: 1855025. DOI: 10.1091/mbc.e06-09-0823. View

18.

Nieto M . Epithelial plasticity: a common theme in embryonic and cancer cells. Science. 2013; 342(6159):1234850. DOI: 10.1126/science.1234850. View

19.

Jolly M, Huang B, Lu M, Mani S, Levine H, Ben-Jacob E . Towards elucidating the connection between epithelial-mesenchymal transitions and stemness. J R Soc Interface. 2014; 11(101):20140962. PMC: 4223923. DOI: 10.1098/rsif.2014.0962. View

20.

Johansson J, Berg T, Kurzejamska E, Pang M, Tabor V, Jansson M . MiR-155-mediated loss of C/EBPβ shifts the TGF-β response from growth inhibition to epithelial-mesenchymal transition, invasion and metastasis in breast cancer. Oncogene. 2013; 32(50):5614-24. PMC: 3898103. DOI: 10.1038/onc.2013.322. View