Research Program Overview
Our laboratory seeks to identify signalling pathways that are dysregulated in cancer that drive cell growth and survival – to discover new biomarkers and therapeutic targets for cancers that lack reliable targeted therapy and to elucidate the mechanisms underlying therapy resistance. Although targeted therapy for many cancers has made huge progress in recent years, triple negative breast cancer in women and the childhood cancer, neuroblastoma, lag many other cancers in this aspect.
- Triple negative breast cancer is breast cancer that lacks oestrogen and progesterone receptors and has no HER2 amplification. As such, to date, unlike the other forms of breast cancer, there is a paucity of reliable targeted therapy to treat triple negative breast cancer and chemotherapy remains the standard of care. However, whilst many patients respond well to chemotherapy, about a quarter to a fifth of patients become resistant to chemotherapy and there are few treatment options thereafter. Consequently, there is a need to understand the underlying causes of chemoresistance in triple negative breast cancer.
Our recent studies have identified a signalling pathway – the Fer-PKCδ-PTPN14 axis – that is dysregulated in about 25-30% of triple negative breast cancer patients. Dysregulation of this pathway leads to increased secretion of pro-metastatic factors (Belle et al., 2015), as well as increased oncogenic signalling and better cell survival due to aberrant receptor trafficking (Lonic et al., 2021).
- Neuroblastoma is a childhood cancer that particularly affects very young children under the age of five, with a median age of diagnosis around one-and-a-half to two years of age. It is a highly heterogeneous cancer of the sympathetic nervous system with some unusual properties that are poorly understood. These include some children with stage 4 cancers that can spontaneously regress without treatment, yet others do not respond to treatment. The lack of reliable targeted therapy for neuroblastoma also means that these children are routinely treated with chemotherapy. However, because of the young age of these patients, even if they recover from the cancer, they can often suffer life-long debilitating outcomes. Our studies are based on the hypothesis that neuroblastoma arise from a failure of complete differentiation of the trunk neural crest cells to sympathetic neurons and it is the intermediate, incompletely differentiated neuroblasts that go on to become cancerous.
Current Research Projects
Triple negative breast cancer
Current projects:
- Investigating how this pathway affects the response of triple negative breast cancer to current treatments, including its role in influencing both the fate of the cancer cells and the tumour microenvironment.
- identifying the molecular mechanisms by which this pathway mediates it effects, including identification of kinase substrates and new (previously under-appreciated) roles of post-translational modifications on kinase functions.
- investigating how dysregulation of the endosomal trafficking mechanisms can lead to cancer progression.
Our laboratory uses phosphoproteomics, functional genomics, spatial transcriptomics, high/super resolution confocal microscopy, genetically modified or xenograft mouse models of triple negative breast cancer and patient breast cancer specimens for our studies.
Neuroblastoma
Current projects:
- will take the approach of understanding the process of differentiation and maturation of neuroblasts to sympathetic neurons to identify critical signalling pathways of the differentiation and maturation program, using induced pluripotent stem cells (iPSCs).
- use data on neuroblast differentiation to identify and understand how dysregulated signalling pathways can lead to neuroblastoma.
- using iPSCs to model the disease to identical potential new therapeutic targets.
These studies will be carried out using state-of-the-art sequencing strategies for coding and non-coding RNAs, bioinformatics and spatial transcriptomics using mouse embryos and patient samples. These studies are part of a large collaborative team which includes those of Associate Professor Quenten Schwarz and Professor Greg Goodall at the Centre for Cancer Biology.
Laboratory staff
Laboratory head
Team Members
Postdoctoral Research Scientists
Research assistants
Technician
Postgraduate Students
- Ms Winona Onglao
winona.onglao@mymail.unisa.edu.au
- Mr Vishnu Sunil Jaikumar
vishnu.sunil_jaikumar@mymail.unisa.edu.au
- Emily Susan Jane Phipps
emily.phipps@mymail.unisa.edu.au
Select Recent Publications
- Aberrant post-translational modifications in endosomal trafficking are potential therapeutic targets to avert therapy resistance in solid cancers: Dysregulation of PTM-regulated endosomal interactions presents an opportunity to block oncogenic signalling from multiple receptors by targeting common trafficking pathways
Onglao W, Khew-Goodall Y, Belle L* and Lonic A*.
Bioessays 2021 Dec 16;e2100192. doi: 10.1002/bies.202100192. - Phosphorylation of PKCδ by FER tips the balance from EGFR degradation to recycling.
Lonic A, Gehling F, Belle L, Li X, Schieber NL, Nguyen EV, Goodall GJ, Parton RG, Daly RJ,
Khew-Goodall Y.
J Cell Biol. 2021 Feb 1;220(2):e201902073. - Guidelines and definitions for research on epithelial-mesenchymal transition.
Yang J, Antin P, Berx G, Blanpain C, Brabletz T, Bronner M, Campbell K, Cano A, Casanova J, Christofori G, Dedhar S, Derynck R, Ford HL, Fuxe J, García de Herreros A, Goodall GJ, Hadjantonakis AK, Huang RJY, Kalcheim C, Kalluri R, Kang Y, Khew-Goodall Y, Levine H, Liu J, Longmore GD, Mani SA, Massagué J, Mayor R, McClay D, Mostov KE, Newgreen DF, Nieto MA, Puisieux A, Runyan R, Savagner P, Stanger B, Stemmler MP, Takahashi Y, Takeichi M, Theveneau E, Thiery JP, Thompson EW, Weinberg RA, Williams ED, Xing J, Zhou BP, Sheng G; EMT International Association (TEMTIA).
Nat Rev Mol Cell Biol. 2020 Apr 16. doi: 10.1038/s41580-020-0237-9. [Epub ahead of print] Review. - Stathmin levels alter PTPN14 expression and impact neuroblastoma cell migration.
Po'uha ST, Le Grand M, Brandl MB, Gifford AJ, Goodall GJ, Khew-Goodall Y, Kavallaris M.
Br J Cancer. 2020 Feb;122(3):434-444. doi: 10.1038/s41416-019-0669-1. Epub 2019 Dec 6. - PTPN14 phosphatase and YAP promote TGFβ signalling in rheumatoid synoviocytes.
Bottini A, Wu DJ, Ai R, Le Roux M, Bartok B, Bombardieri M, Doody KM, Zhang V, Sacchetti C, Zoccheddu M, Lonic A, Li X, Boyle DL, Hammaker D, Meng TC, Liu L, Corr M, Stanford SM, Lewis M, Wang W, Firestein GS, Khew-Goodall Y, Pitzalis C, Bottini N.
Ann Rheum Dis. 2019 May;78(5):600-609. doi: 10.1136/annrheumdis-2018-213799. Epub 2019 Feb 26. - miR-200/375 control epithelial plasticity-associated alternative splicing by repressing the RNA-binding protein Quaking.
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.
EMBO J. 2018 Jul 2;37(13). pii: e99016. doi: 10.15252/embj.201899016. Epub 2018 Jun 5. - Network-Based Approaches to Understand the Roles of miR-200 and Other microRNAs in Cancer.
Bracken CP, Khew-Goodall Y, Goodall GJ.
Cancer Res. 2015 Jul 1;75(13):2594-9. doi: 10.1158/0008-5472.CAN-15-0287. Epub 2015 Jun 11. Review. - The tyrosine phosphatase PTPN14 (Pez) inhibits metastasis by altering protein trafficking.
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, Khew-Goodall Y.
Sci Signal. 2015 Feb 17;8(364):ra18. doi: 10.1126/scisignal.2005547. - Genome-wide identification of miR-200 targets reveals a regulatory network controlling cell invasion.
Bracken CP, Li X, Wright JA, Lawrence DM, 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.
EMBO J. 2014 Sep 17;33(18):2040-56. doi: 10.15252/embj.201488641. Epub 2014 Jul 28. - Identification of an enhancer that increases miR-200b~200a~429 gene expression in breast cancer cells.
Attema JL, Bert AG, Lim YY, Kolesnikoff N, Lawrence DM, Pillman KA, Smith E, Drew PA, Khew-Goodall Y, Shannon F, Goodall GJ.
PLoS One. 2013 Sep 25;8(9):e75517. doi: 10.1371/journal.pone.0075517. eCollection 2013. - MiR-200 can repress breast cancer metastasis through ZEB1-independent but moesin-dependent pathways.
Li X, Roslan S, Johnstone CN, Wright JA, Bracken CP, Anderson M, Bert AG, Selth LA, Anderson RL, Goodall GJ, Gregory PA, Khew-Goodall Y.
Oncogene. 2014 Jul 31;33(31):4077-88. doi: 10.1038/onc.2013.370. Epub 2013 Sep 16. - The secretome in cancer progression.
Paltridge JL, Belle L, Khew-Goodall Y.
Biochim Biophys Acta. 2013 Nov;1834(11):2233-41. doi: 10.1016/j.bbapap.2013.03.014. Epub 2013 Mar 28. Series Editor R Simpson. Invited review. - Epigenetic modulation of the miR-200 family is associated with transition to a breast cancer stem-cell-like state.
Lim YY, Wright JA, Attema JL, Gregory PA, Bert AG, Smith E, Thomas D, Lopez AF, Drew PA, Khew-Goodall Y, Goodall GJ.
J Cell Sci. 2013 May 15;126(Pt 10):2256-66. doi: 10.1242/jcs.122275. Epub 2013 Mar 22. - Down-regulation of the miRNA-200 family at the invasive front of colorectal cancers with degraded basement membrane indicates EMT is involved in cancer progression.
Paterson EL, Kazenwadel J, Bert AG, Khew-Goodall Y, Ruszkiewicz A, Goodall GJ.
Neoplasia. 2013 Feb;15(2):180-91. - An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition.
Gregory PA, Bracken CP, Smith E, Bert AG, Wright JA, Roslan S, Morris M, Wyatt L, Farshid G, Lim YY, Lindeman GJ, Shannon MF, Drew PA, Khew-Goodall Y, Goodall GJ.
Mol Biol Cell. 2011 May 15;22(10):1686-98. doi: 10.1091/mbc.E11-02-0103. Epub 2011 Mar 16. - The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1
Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y*, Goodall GJ*. *equal senior authors.
Nat Cell Biol. 2008 May;10(5):593-601. doi: 10.1038/ncb1722. Epub 2008 Mar 30. - The protein tyrosine phosphatase Pez regulates TGFbeta, epithelial-mesenchymal transition, and organ development.
Wyatt L, Wadham C, Crocker LA, Lardelli M, Khew-Goodall Y.
J Cell Biol. 2007 Sep 24;178(7):1223-35. doi: 10.1083/jcb.200705035.
