Jane Antony

All Publications

• The tumour suppressor OPCML promotes AXL inactivation by the phosphatase PTPRG in ovarian cancer EMBO Reports Antony, J., Zanini, E., Kelly, ., Tan, T. Z., Karali, E., Alomary, M., Jung, Y., Nixon, K., Cunnea, P., Fotopoulou, C., Paterson, A., Roy‐Nawathe, S., Mills, G. B., Huang, R. Y., Thiery, J., Gabra, H., Recchi, C. 2018

  Abstract

  In ovarian cancer, the prometastatic RTK AXL promotes motility, invasion and poor prognosis. Here, we show that reduced survival caused by AXL overexpression can be mitigated by the expression of the GPI-anchored tumour suppressor OPCML Further, we demonstrate that AXL directly interacts with OPCML, preferentially so when AXL is activated by its ligand Gas6. As a consequence, AXL accumulates in cholesterol-rich lipid domains, where OPCML resides. Here, phospho-AXL is brought in proximity to the lipid domain-restricted phosphatase PTPRG, which de-phosphorylates the RTK/ligand complex. This prevents AXL-mediated transactivation of other RTKs (cMET and EGFR), thereby inhibiting sustained phospho-ERK signalling, induction of the EMT transcription factor Slug, cell migration and invasion. From a translational perspective, we show that OPCML enhances the effect of the phase II AXL inhibitor R428 in vitro and in vivo We therefore identify a novel mechanism by which two spatially restricted tumour suppressors, OPCML and PTPRG, coordinate to repress AXL-dependent oncogenic signalling.

  View details for DOI 10.15252/embr.201745670

  View details for PubMedCentralID PMC6073217

• Synergistic inactivation of AXL: a (cross)road to cure ovarian cancer? EMBO reports Zurzolo, C. 2018

  View details for DOI 10.15252/embr.201846492

  View details for PubMedID 29967225

• The Tumor-Suppressor Protein OPCML Potentiates Anti-EGFR- and Anti-HER2-Targeted Therapy in HER2-Positive Ovarian and Breast Cancer MOLECULAR CANCER THERAPEUTICS Zanini, E., Louis, L. S., Antony, J., Karali, E., Okon, I. S., Mckie, A. B., Vaughan, S., El-Bahrawy, M., Stebbing, J., Recchi, C., Gabra, H. 2017; 16 (10): 2246–56

  Abstract

  Opioid-binding protein/cell adhesion molecule-like (OPCML) is a tumor-suppressor gene that is frequently inactivated in ovarian cancer and many other cancers by somatic methylation. We have previously shown that OPCML exerts its suppressor function by negatively regulating a spectrum of receptor tyrosine kinases (RTK), such as ErbB2/HER2, FGFR1, and EphA2, thus attenuating their related downstream signaling. The physical interaction of OPCML with this defined group of RTKs is a prerequisite for their downregulation. Overexpression/gene amplification of EGFR and HER2 is a frequent event in multiple cancers, including ovarian and breast cancers. Molecular therapeutics against EGFR/HER2 or EGFR only, such as lapatinib and erlotinib, respectively, were developed to target these receptors, but resistance often occurs in relapsing cancers. Here we show that, though OPCML interacts only with HER2 and not with EGFR, the interaction of OPCML with HER2 disrupts the formation of the HER2-EGFR heterodimer, and this translates into a better response to both lapatinib and erlotinib in HER2-expressing ovarian and breast cancer cell lines. Also, we show that high OPCML expression is associated with better response to lapatinib therapy in breast cancer patients and better survival in HER2-overexpressing ovarian cancer patients, suggesting that OPCML co-therapy could be a valuable sensitizing approach to RTK inhibitors. Mol Cancer Ther; 16(10); 2246-56. ©2017 AACR.

  View details for DOI 10.1158/1535-7163.MCT-17-0081

  View details for Web of Science ID 000412220900018

  View details for PubMedID 28775148

• AXL-Driven EMT State as a Targetable Conduit in Cancer CANCER RESEARCH Antony, J., Huang, R. 2017; 77 (14): 3725–32

  Abstract

  The receptor tyrosine kinase (RTK) AXL has been intrinsically linked to epithelial-mesenchymal transition (EMT) and promoting cell survival, anoikis resistance, invasion, and metastasis in several cancers. AXL signaling has been shown to directly affect the mesenchymal state and confer it with aggressive phenotype and drug resistance. Recently, the EMT gradient has also been shown to rewire the kinase signaling nodes that facilitate AXL-RTK cross-talk, protracted signaling, converging on ERK, and PI3K axes. The molecular mechanisms underplaying the regulation between the kinome and EMT require further elucidation to define targetable conduits. Therapeutically, as AXL inhibition has shown EMT reversal and resensitization to other tyrosine kinase inhibitors, mitotic inhibitors, and platinum-based therapy, there is a need to stratify patients based on AXL dependence. This review elucidates the role of AXL in EMT-mediated oncogenesis and highlights the reciprocal control between AXL signaling and the EMT state. In addition, we review the potential in inhibiting AXL for the development of different therapeutic strategies and inhibitors. Cancer Res; 77(14); 3725-32. ©2017 AACR.

  View details for DOI 10.1158/0008-5472.CAN-17-0392

  View details for Web of Science ID 000405677500001

  View details for PubMedID 28667075

• Targeting the AXL signaling pathway in ovarian cancer MOLECULAR & CELLULAR ONCOLOGY Huang, R., Antony, J., Tan, T., Tan, D. 2017; 4 (2): e1263716

  Abstract

  In a recent publication in Science Signaling, we showed that a Mes molecular subtype of epithelial ovarian cancer (EOC) harboring epithelial-mesenchymal transition (EMT) features has a unique signaling network downstream of the GAS6/AXL pathway. Our finding leads to a potential strategy for treating the Mes subtype of EOC by targeting AXL.

  View details for DOI 10.1080/23723556.2016.1263716

  View details for Web of Science ID 000406843600014

  View details for PubMedID 28401178

  View details for PubMedCentralID PMC5383361

• The GAS6-AXL signaling network is a mesenchymal (Mes) molecular subtype-specific therapeutic target for ovarian cancer SCIENCE SIGNALING Antony, J., Tan, T., Kelly, Z., Low, J., Choolani, M., Recchi, C., Gabra, H., Thiery, J., Huang, R. 2016; 9 (448): ra97

  Abstract

  Ovarian cancer is a complex disease with heterogeneity among the gene expression molecular subtypes (GEMS) between patients. Patients with tumors of a mesenchymal ("Mes") subtype have a poorer prognosis than patients with tumors of an epithelial ("Epi") subtype. We evaluated GEMS of ovarian cancer patients for molecular signaling profiles and assessed how the differences in these profiles could be leveraged to improve patient clinical outcome. Kinome enrichment analysis identified AXL as a particularly abundant kinase in Mes-subtype tumor tissue and cell lines. In Mes cells, upon activation by its ligand GAS6, AXL coclustered with and transactivated the receptor tyrosine kinases (RTKs) cMET, EGFR, and HER2, producing sustained extracellular signal-regulated kinase (ERK) activation. In Epi-A cells, AXL was less abundant and induced a transient activation of ERK without evidence of RTK transactivation. AXL-RTK crosstalk also stimulated sustained activation of the transcription factor FRA1, which correlated with the induction of the epithelial-mesenchymal transition (EMT)-associated transcription factor SLUG and stimulation of motility exclusively in Mes-subtype cells. The AXL inhibitor R428 attenuated RTK and ERK activation and reduced cell motility in Mes cells in culture and reduced tumor growth in a chick chorioallantoic membrane model. A higher concentration of R428 was needed to inhibit ERK activation and cell motility in Epi-A cells. Silencing AXL in Mes-subtype cells reversed the mesenchymal phenotype in culture and abolished tumor formation in an orthotopic xenograft mouse model. Thus, AXL-targeted therapy may improve clinical outcome for patients with Mes-subtype ovarian cancer.

  View details for DOI 10.1126/scisignal.aaf8175

  View details for Web of Science ID 000387027200002

  View details for PubMedID 27703030

• New twists in the AXL(e) of tumor progression SCIENCE SIGNALING Halmos, B., Haura, E. B. 2016; 9 (448): fs14

  Abstract

  Patients with a mesenchymal subtype of ovarian cancer face a poor prognosis with limited treatment options to halt metastatic progression. In this issue of Science Signaling, Antony et al found that the kinase AXL drives the mesenchymal gene signature and motility of ovarian tumor cells. AXL inhibitors may thus slow tumor progression in this subset of patients.

  View details for DOI 10.1126/scisignal.aai7619

  View details for Web of Science ID 000387027200001

  View details for PubMedID 27703029

• Sustained Gas6/AXL signaling network in the mes subtype of ovarian cancer as a molecular subtype specific therapeutic target. Huang, R., Antony, J., Tan, T., Kelly, Z., Gabra, H., Recchi, C., Thiery, J. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.e17084

  View details for Web of Science ID 000404711502095