Gene Regulation Section
The major cause of death from most cancers is metastasis, a process whereby cells migrate away from the primary tumour. Cancer cells become metastatic and invasive through a process known as epithelial to mesenchymal transition (EMT). One of our key discoveries has been that EMT is controlled by the miR-200 family of microRNAs (small RNA molecules regulating many key processes in the cell). Our research is focused in this area.
We have found in our in-vitro models that the microRNAs have to be turned off to allow the cells to become migratory and invasive. We have also found that if we enforce expression of the microRNAs, we can block the EMT process and even convert the migratory cells back to non-migratory, ‘epithelial’ cells. These are exciting discoveries.
In ongoing work we are examining the mechanisms that control production and loss of the microRNAs; identifying the gene targets of the microRNAs; examining human tumours for involvement of the microRNAs in invasion and metastasis and using in vitro and in vivo models to identify the pathways through which they operate. We are also using next-gen sequencing to identify the involvement of microRNAs in other important biological processes and diseases.
A further exciting development is our discovery that circular RNAs are regulated during EMT. Circular RNAs are a form of non-coding RNA that has only recently been recognised but are implicated in controlling microRNA function and in other processes. We are examining aspects of circRNA formation and function in EMT.
Current research projects
- Characterising the interactions between microRNAs and their targets
- Control of alternative splicing during EMT
- Epigenetic control of genes in EMT
- Interactions between microRNAs and transcription factors in EMT
- Formation and function of circRNAs in EMT
Selected recent publications
Bracken CP, Khew-Goodall Y, Goodall GJ. Network-based Approaches to Understand the Roles of miR-200 and Other MicroRNAs in Cancer. Cancer Res. 75:2594-2599, 2015 PMID: 26069247
Pal B, Chen Y, Bert AG, Hu Y, Beck T, Sheridan JM, Shi W, Satterley K, Jamieson P, Goodall GJ, Lindeman GL, Smyth GK and Visvader JE. Integration of microRNA signatures of distinct mammary epithelial cell types with their gene expression and epigenetic portraits. Breast Cancer Res. 17:85, 2015. PMID: 26080807.
Narayan N, Morenos L, Phipson B, Willis SN, Brumatti G, Eggers S, Lalaoui N, Brown LM, Kosasih HJ, Bartolo RC, Zhou L, Catchpoole D, Saffery R, Oshlack A, Goodall GJ, Ekert PG. Functionally distinct roles for different miR-155 expression levels through contrasting effects on gene expression, in acute myeloid leukemia. Leukemia [Epub ahead of print] 2016 PMID: 27740637
Bracken CP, Scott HS, Goodall GJ. A network-biology perspective of microRNA function and dysfunction in cancer. Nat Rev Genet.17:719-732, 2016. PMID: 27795564
Das R, Gregory PA, Fernandes RC, Denis I, Wang Q, Townley SL, Zhao SG, Hanson A, Pickering MA, Armstrong HK, Lokman NA, Ebrahimie E, Davicioni E, Jenkins RB, Karnes RJ, Ross AE, Den RB, Klein EA, Chi KN, Ramshaw HS, Williams ED, Zoubedi A, Goodall GJ, Feng FY, Butler LM, Tilley WD, Selth LA. MicroRNA-194 promotes prostate cancer metastasis by inhibiting SOCS2. Cancer Res. 2016 [Epub ahead of print] PMID: 28011622
Selth LA, Townley SL, Das R, Coutinho I, Hanson AR, Centenera MM, Butler LM, StylianouN, Sweeney K, Soekmadji C, Jovanovic L, Nelson CC, Zoubeidi A, Butler LM, Goodall GJ, Hollier BG, Gregory PA and Tilley WD. A ZEB1-miR-375-YAP1 pathway controls epithelial plasticity in prostate cancer. Oncogene 36:24-342017. PMID: 27270433
Conn SJ, Pillman KA, Toubia J, Conn VM, Salmanidis M, Phillips CA, Roslan S, Schreiber AW, Gregory PA and Goodall GJ. The RNA binding protein Quaking regulates formation of circRNAs. Cell 160:1125-1134, 2015.
Belle L, Ali N, Lonic A, Li X, Paltridge JL, Roslan S, Herrmann D, Conway JR, Gehling FK, Bert AG, Crocker LA, Tsykin A, Farshid G, Goodall GJ, Timpson P, Daly RJ and Khew-Goodall Y. The tyrosine phosphatase PTPN14 (Pez) inhibits metastasis by altering protein trafficking. Science Signaling 8(364):ra18, 2015 PMID: 25690013
Bracken CP, Li X, Wright JA, Lawrence D, Pillman KA, Salmanidis M, Anderson MA, Dredge BK, Gregory PA, Tsykin A, Neilsen C, Thomson DW, Bert AG, Leerberg JM, Yap AS, Jensen KB, Khew-Goodall Y, Goodall GJ. Genome-wide identification of miR-200 targets reveals a regulatory network controlling cell invasion. EMBO J. 33:2040-2056, 2014. PMID: 25069772.
Thomson DW, Pillman KA, Anderson ML, Lawrence DL, Toubia J, Goodall GJ*, Bracken CP*. Assessing the gene regulatory properties of Argonaute-bound small RNAs of diverse genomic origin. Nucl Acids Res 43:470-481, 2015. PMID: 25452337
Salmanidis M, Pillman K, Goodall G, Bracken C. Direct transcriptional regulation by nuclear microRNAs. Int J Biochem Cell Biol. 2014 Mar 25. pii: S1357-2725(14)00085-5. [Epub ahead of print] Review.
Kolesnikoff N, Attema JA, Roslan S, Bert AG, Schwarz QP, Gregory PA, Goodall GJ. Specificity Protein 1 (Sp1) maintains basal epithelial expression of the miR-200 family: implications for epithelial-mesenchymal transition. J Biol Chem 289:11194-11205, 2014. PMID: 24627491
Li X, Roslan S, Johnstone CN, Wright JA, Bracken CP, Anderson M, Bert AG, Selth LA, Anderson RA, Goodall GJ, Gregory PA, Khew-Goodall Y. MiR-200 can repress breast cancer metastasis through ZEB1-independent, but moesin-dependent pathways. Oncogene Jul 31;33(31):4077-88 2014 PMID: 24037528
Attema JL, Bert AG, Lim YY, Kolesnikoff N, Lawrence DM, Pillman KA, Smith E, Drew PA, Khew-Goodall Y, Shannon MF, Goodall GJ. Identification of an enhancer that controls miR-200b~200a~429 gene expression in breast cancer cells. PlosOne 8, e75517, 2013 PMID: 24086551
Lim YY, Wright JA, Attema JA, Gregory PA, Bert AG, Smith E, Thomas D, Lopez AF, Drew PA, Khew-Goodall Y and Goodall GJ. Epigenetic modulation of the miR-200 family is associated with transition to a breast cancer stem cell-like state. J. Cell Sci. 126:2256-2266, 2013. PMID: 23525011
Le TD, Liu L, Tsykin A, Goodall GJ, Liu B, Sun B_Y, and Li J. Inferring microRNA-mRNA causal regulatory relationships from expression data. Bioinformatics 29:765-771, 2013
Thomson DW, Bracken CP, Szubert JM, Goodall GJ. On measuring miRNAs after transient transfection of mimics or antisense inhibitors. PlosOne 8:e55214, 2013
Paterson EL, Kazenwadel J, Bert AG, Khew-Goodall Y, Ruszkiewicz A, Goodall GJ Downregulation of the miRNA-200 family at the invasive front of colorectal cancers with degraded basement membrane indicates EMT is involved in cancer progression. Neoplasia 15:180-191, 2013 PMID: 23441132
Neilsen CT, Goodall GJ and Bracken CP. IsomiRs - the overlooked repertoire that contributes to the dynamic microRNAome. Trends in Genetics 28: 544-549, 2012
Khew-Goodall Y and Goodall GJ. Stromal miR-320 keeps an oncogenic secretome in check. Nature Cell Biol. 14:124-125, 2012
Thomson DW, Bracken CP, Goodall GJ. Experimental strategies for microRNA target identification. Nucleic Acids Res. 39:6845-6853, 2011
Gregory PA, Bracken CP, Smith E, Bert AG, Wright JA, Roslan S, Morris M, Wyatt L, Lim YY, Farshid G, Lindeman GJ, Shannon MF, Drew PA, Khew-Goodall Y, Goodall GJ. An autocrine miR-200/ZEB/TGF-β signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. Mol. Biol. Cell 22:1686-1698. 2011 (Journal Cover Feature)
Bracken CP, Szubert JM, Mercer TR, Dinger ME, Thomson DW, Mattick JS, Michael MZ, Goodall, GJ. Global analysis of the mammalian RNA degradome reveals widespread miRNA-dependent and miRNA-independent endonucleolytic cleavage. Nucl. Acids Res. 39:5658-5668, 2011
Liu B, Liu L, Tsykin A, Goodall GJ, Green JE, Zhu M, Kim CH, Li J. Identifying functional miRNA-mRNA regulatory modules with Correspondence Latent Dirichlet Allocation. Bioinformatics 26:3105-3111, 2010
Khew-Goodall Y, Goodall GJ. Myc-modulated miR-9 makes more metastases, Nature Cell Biol. 12:209-211, 2010
Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, Shannon MF, Goodall GJ. A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 68: 7846-7854, 2008
Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ. The microRNA-200 family and miR-205 regulate epithelial-mesenchymal transition by targeting the E-cadherin repressors, ZEB1 and SIP1. Nature Cell Biol. 10;593-601, 2008