Gene Regulation in Cancer Group
In the last decade, our conception of the complexity of the mammalian transcriptome has been revolutionized by the annotation of the human genome and the advent of deep sequencing technologies. It is now clear that the majority of the genome is transcribed into protein-coding and non-coding regulatory RNAs, however the functional consequences of the majority of these RNAs remains unknown.
During cancer progression, tumour cells undergo significant changes in cellular function. For epithelial tumour cells to metastasise they must acquire abilities to invade, survive and then colonise distant sites.
Epithelial cell plasticity (or epithelial-mesenchymal transition) plays a major role in the metastatic cascade. Our lab is examining how EMT and cancer metastasis are regulated by non-coding RNAs. In particular, our research focusses on how microRNAs alter the cancer cell transcriptome using in vitro and in vivo cancer models coupled with next generation sequencing.
Current research projects
Contribution of alternative splicing to cellular plasticity and cancer progression.
Despite almost all genes having alternative isoforms the functional consequences of most have not been assessed. Using in vitro models, we have characterised global changes in alternative splicing during EMT. We are examining how these events are regulated, and their on breast and prostate cancer progression using CRISPR based genome editing.
MicroRNA regulation of breast cancer metastasis
Breast cancer is a heterogeneous disease, with progression to invasive subtypes correlating with poor clinical outcome. We have identified microRNAs that distinguish highly metastatic from less metastatic breast tumours and are examining their function and therapeutic potential using in vivo mouse models.
Pillman KA, Scheer KG, Hackett-Jones E, Saunders K, Bert AG, Toubia J, Whitfield HJ, Sapkota S, Sourdin L, Pham H, Le TD, Cursons J, Davis MJ, Gregory PA, Goodall GJ, Bracken CP (2019) Extensive transcriptional responses are co-ordinated by microRNAs as revealed by Exon-Intron Split Analysis (EISA). Nucleic Acids Research Aug 2. pii: gkz664. doi: 10.1093/nar/gkz664.
Gregory PA (2019) The miR-200-Quaking axis functions in tumour angiogenesis. Oncogene. 2019 38(41):6767-6769.
Pillman KA, Phillips CA, Roslan S, Toubia J, Dredge BK, Bert AG, Lumb R, Neumann DP, Li X, Conn SJ, Liu D, Bracken CP, Lawrence DM, Stylianou N, Schreiber AW, Tilley WD, Hollier BG, Khew-Goodall Y, Selth LA, Goodall GJ, Gregory PA (2018) miR-200/375 controls epithelial plasticity-associated alternative splicing by repressing the RNA-binding protein Quaking. EMBO J. Jul 2;37(13). pii: e99016.
Cursons J, Pillman KA, Scheer K, Gregory PA, Foroutan M, Zadeh SH, Toubia J, Crampin EJ, Goodall GJ, Bracken CP, Davis MJ (2018) Combinatorial targeting by microRNAs coordinates post-transcriptional control of EMT. Cell Systems Jul 25;7(1):77-91.e7.
Gomez GA, Woodcock JM, Tergaonkar V, Gregory PA (2018) Meeting Report: The 8th Barossa Meeting-Cell Signaling in Cancer Medicine in the Barossa Valley, Australia. Cell Death Dis. 2018 Feb 15;9(3):284.
Neumann DP, Goodall GJ, Gregory PA (2018) Regulation of splicing and circularisation of RNA in epithelial mesenchymal plasticity. Semin. Cell Dev. Biol. 75:50-60.
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. 77(4):1021-1034. 2017
Tse BW, Volpert M, Ratther E, Stylianou N, Nouri M, McGowan K, Lehman ML, McPherson SJ, Roshan-Moniri M, Butler MS, Caradec J, Gregory-Evans CY, McGovern J, Das R, Takhar M, Erho N, Alshalafa M, Davicioni E, Schaeffer EM, Jenkins RB, Ross AE, Karnes RJ, Den RB, Fazli L, Gregory PA, Gleave ME, Williams ED, Rennie PS, Buttyan R, Gunter JH, Selth LA, Russell PJ, Nelson CC, Hollier BG. Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality. Oncogene doi: 10.1038/onc.2016.482. [Epub ahead of print] 2017
Selth LA, Townley SL, Das R, Coutinho I, Hanson AR, Centenera MM, Butler LM, Stylianou N, 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(1):24-34. 2017
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
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
Das R*, Gregory PA*, Hollier BG, Tilley WD, Selth LA. Epithelial plasticity in prostate cancer: principles and clinical perspectives. Trends Mol Med..pii: S1471-4914(14)00141-5. 2014 *Equal contribution
Kolesnikoff N, Attema JL, 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. Apr 18;289(16):11194-205. 2014 *Equal contribution
Li X, Roslan S, Johnstone CN, Wright JA, Bracken CP, Anderson M, Bert AG, Selth LA, Robin Anderson RL, Goodall GJ, Gregory PA*, Khew-Goodall Y* MiR-200 can repress breast cancer metastasis through ZEB1-independent, but moesin-dependent pathways. Oncogene 33(31):4077-88. 2014 *Equal contribution
Lim YY, Wright JA, Attema JL, Gregory PA, Bert AG, Smith E, Thomas D, Lopez AF, Drew PA, Khew-Goodall Y, Goodall GJ Epigenetic modulation of the miR-200 family is associated with transition to a breast cancer stem-cell-like state. J Cell Sci. 126:2256-66. 2013
Ahn YH, Gibbons DL, Chakravarti D, Creighton CJ, Rizvi ZH, Adams HP, Pertsemlidis A, Gregory PA, Wright JA, Goodall GJ, Flores ER, Kurie JM ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression. J Clin Invest. 122(9):3170-83. 2012
Gregory PA, Bracken CP, Smith E, Bert AG, Wright JA, Roslan S, Morris M, Wyatt L, Farshid G, Lim Y-Y, Lindeman GJ, Shannon MF, Drew PA, Khew-Goodall Y, Goodall GJ (2011) An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. Mol Biol Cell 22(10):1686-98. 2011 * Featured front cover article.
Bracken CP*, Gregory PA*, Kolesnikoff N, Bert AG, Shannon MF, Goodall GJ (2008) A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 68 (19): 7846-7854. 2008 *Equal contribution
Gregory PA, Bracken CP, Bert AG, Goodall GJ MicroRNAs as regulators of epithelial-mesenchymal transition. Cell Cycle 7(20):3112-18. 2008
Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ The mir-200 family and mir-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nature Cell Biol. 10, 593-601. 2008