Honors & Awards
Dean’s Postdoctoral Fellowship, Stanford University (July 2018 - June 2019)
NGS Graduate Scholarship, National University of Singapore - Imperial College London (August 2012 - July 2016)
Boards, Advisory Committees, Professional Organizations
Postdoctoral member, American Society for Cell Biology (ASCB) (2018 - Present)
Member, TEMTIA, The EMT International Association (2018 - Present)
Associate member, American Association for Cancer Research (2018 - Present)
Young Investigator membership, Eauropean Association for Cancer Research (EACR) (2018 - Present)
Doctor of Philosophy, National University Of Singapore (2017)
Bachelor of Engineering, National University Of Singapore (2012)
Doctor of Philosophy, Imperial College of Science, Technology & Medicine (2017)
Michael F. Clarke, Neethan A. Lobo, Maider Zabala Ugalde, Jane Antony. "United States Patent 103182-1086502-000501US COMPOSITIONS AND METHODS FOR MODULATING LEFTY AND BMP PROTEINS", Chan Zuckerberg Biohub, The Board Of Trustees Of The Leland Stanford Junior University
Current Research and Scholarly Interests
Although varying degrees of progress has been made to treat the heterogenous subtypes of breast cancers, metastasis and recurrence remains a major cause of breast cancer-related deaths. My research focuses on drivers of tumor growth and testing new targets for these breast cancers to prevent metastasis and recurrence; specifically, profiling and validating genes enriched in the self-renewing tumorigenic compartment.
LEFTY1 Is a Dual-SMAD Inhibitor that Promotes Mammary Progenitor Growth and Tumorigenesis.
Cell stem cell
SMAD pathways govern epithelial proliferation, and transforming growth factor beta (TGF-beta and BMP signaling through SMAD members has distinct effects on mammary development and homeostasis. Here, we show that LEFTY1, a secreted inhibitor of NODAL/SMAD2 signaling, is produced by mammary progenitor cells and, concomitantly, suppresses SMAD2 and SMAD5 signaling to promote long-term proliferation of normal and malignant mammary epithelial cells. In contrast, BMP7, a NODAL antagonist with context-dependent functions, is produced by basal cells and restrains progenitor cell proliferation. In normal mouse epithelium, LEFTY1 expression in a subset of luminal cells and rare basal cells opposes BMP7 to promote ductal branching. LEFTY1 binds BMPR2 to suppress BMP7-induced activation of SMAD5, and this LEFTY1-BMPR2 interaction is specific to tumor-initiating cells in triple-negative breast cancer xenografts that rely on LEFTY1 for growth. These results suggest that LEFTY1 is an endogenous dual-SMAD inhibitor and that suppressing its function may represent a therapeutic vulnerability in breast cancer.
View details for DOI 10.1016/j.stem.2020.06.017
View details for PubMedID 32693087
Emerging roles for the GPI-anchored tumor suppressor OPCML in cancers.
Cancer gene therapy
OPCML is a highly conserved glycosyl phosphatidylinositol (GPI)-anchored protein belonging to the IgLON family of cell adhesion molecules. OPCML functions as a tumor suppressor and is silenced in over 80% of ovarian cancers by loss of heterozygosity and by epigenetic mechanisms. OPCML inactivation is also observed in many other cancers suggesting a conservation of tumor suppressor function. Although epigenetic silencing and subsequent loss of OPCML expression correlate with poor progression-free and overall patient survival, its mechanism of action is only starting to be fully elucidated. Recent discoveries have demonstrated that OPCML exerts its tumor suppressor effect by inhibiting several cancer hallmark phenotypes in vitro and abrogating tumorigenesis in vivo, by downregulating/inactivating a specific spectrum of Receptor Tyrosine Kinases (RTKs), including EphA2, FGFR1, FGFR3, HER2, HER4, and AXL. This modulation of RTKs can also sensitize ovarian and breast cancers to lapatinib, erlotinib, and anti-AXL therapies. Furthermore, OPCML has also been shown to function in synergy with the tumor suppressor phosphatase PTPRG to inactivate pro-metastatic RTKs such as AXL. Recently, the identification of inactivating point mutations and the elucidation of the crystal structure of OPCML have provided valuable insights into its structure-function relationships, giving rise to its potential as an anti-cancer therapeutic.
View details for DOI 10.1038/s41417-020-0187-6
View details for PubMedID 32595215
Ageing hallmarks exhibit organ-specific temporal signatures.
Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified-such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function1-these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus, and integrated these findings with data from the accompanying Tabula Muris Senis2-or 'Mouse Ageing Cell Atlas'-which follows on from the original Tabula Muris3. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions-including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue-including plasma cells that express immunoglobulin J-which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age.
View details for DOI 10.1038/s41586-020-2499-y
View details for PubMedID 32669715
- Epithelial-to-mesenchymal transition: lessons from development, insights into cancer and the potential of EMT-subtype based therapeutic intervention PHYSICAL BIOLOGY 2019; 16 (4)
Epithelial-to-mesenchymal transition: Lessons from development, insights into cancer and the potential of EMT-subtype based therapeutic intervention.
Epithelial-to-mesenchymal transition (EMT) is a fundamental developmental process wherein polarized epithelial cells lose their junctional architecture and apical-basal polarity to become motile mesenchymal cells, and there is emerging evidence for its role in propagating tumor dissemination. While many multifaceted nodules converge onto the EMT program, in this review we will highlight the fundamental biology of the signaling schemas that enable EMT. In many cancers, the property of tumor dissemination and metastasis is closely associated with re-enabling developmental properties such as EMT. We discuss the molecular complexity of the tumor heterogeneity in terms of EMT-based gene expression molecular subtypes, and the rewiring of critical signaling nodules in the subtypes displaying higher degrees of EMT can be therapeutically exploited. Specifically in the context of a deadly malignancy such as ovarian cancer where there are no defined mutations or limited biomarkers for developing targeted therapy or personalized medicine, we highlight the importance of identifying EMT-based subtypes that will improve therapeutic intervention. In ovarian cancer, the poor prognosis mesenchymal 'Mes' subtype presents with amplified signaling of the receptor tyrosine kinase (RTK) AXL, extensive crosstalk with other RTKs such as cMET, EGFR and HER2, and sustained temporal activation of Extracellular-signal Regulated Kinase (ERK) leading to induction of EMT transcription factor Slug, underscoring a pathway addiction in Mes that can be therapeutically targeted. We will further examine the emergence of therapeutic modalities in these EMT subtypes and finally conclude with potential interdisciplinary biophysical methodologies to provide additional insights in deciphering the mechanistic and biochemical aspects of EMT.
View details for PubMedID 30939460
Usp16 modulates Wnt signaling in primary tissues through Cdkn2a regulation.
2018; 8 (1): 17506
Regulation of the Wnt pathway in stem cells and primary tissues is still poorly understood. Here we report that Usp16, a negative regulator of Bmi1/PRC1 function, modulates the Wnt pathway in mammary epithelia, primary human fibroblasts and MEFs, affecting their expansion and self-renewal potential. In mammary glands, reduced levels of Usp16 increase tissue responsiveness to Wnt, resulting in upregulation of the downstream Wnt target Axin2, expansion of the basal compartment and increased in vitro and in vivo epithelial regeneration. Usp16 regulation of the Wnt pathway in mouse and human tissues is at least in part mediated by activation of Cdkn2a, a regulator of senescence. At the molecular level, Usp16 affects Rspo-mediated phosphorylation of LRP6. In Down's Syndrome (DS), triplication of Usp16 dampens the activation of the Wnt pathway. Usp16 copy number normalization restores normal Wnt activation in Ts65Dn mice models. Genetic upregulation of the Wnt pathway in Ts65Dn mice rescues the proliferation defect observed in mammary epithelial cells. All together, these findings link important stem cell regulators like Bmi1/Usp16 and Cdkn2a to Wnt signaling, and have implications for designing therapies for conditions, like DS, aging or degenerative diseases, where the Wnt pathway is hampered.
View details for PubMedID 30504774
- Synergistic inactivation of AXL: a (cross)road to cure ovarian cancer? EMBO reports 2018
The tumour suppressor OPCML promotes AXL inactivation by the phosphatase PTPRG in ovarian cancer
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
The Tumor-Suppressor Protein OPCML Potentiates Anti-EGFR- and Anti-HER2-Targeted Therapy in HER2-Positive Ovarian and Breast Cancer
MOLECULAR CANCER THERAPEUTICS
2017; 16 (10): 2246–56
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
2017; 77 (14): 3725–32
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
2017; 4 (2): e1263716
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
2016; 9 (448): ra97
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
2016; 9 (448): fs14
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. AMER SOC CLINICAL ONCOLOGY. 2016