Publications
107 results found
Lucchiari G, Zhang H, Nunes J, et al., 2016, Role of phosphorylation in Lmtk3 activation and its contribution in breast cancer progression, AACR 107th Annual Meeting on Bioinformatics and Systems Biology, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Wendler F, Stamp GW, Giamas G, 2016, Tumor-Stromal Cell Communication: Small Vesicles Signal Big Changes, TRENDS IN CANCER, Vol: 2, Pages: 326-329, ISSN: 2405-8025
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- Citations: 26
Nunes J, Zhang H, Angelopoulos N, et al., 2016, ATG9A loss confers resistance to trastuzumab via c-Cbl mediated Her2 degradation, Oncotarget, Vol: 7, Pages: 27599-27612, ISSN: 1949-2553
Acquired or de novo resistance to trastuzumab remains a barrier to patient survival and mechanisms underlying this still remain unclear. Using stable isotope labelling by amino acids in cell culture (SILAC)-based quantitative proteomics to compare proteome profiles between trastuzumab sensitive/resistant cells, we identified autophagy related protein 9A (ATG9A) as a down-regulated protein in trastuzumab resistant cells (BT474-TR). Interestingly, ATG9A ectopic expression markedly decreased the proliferative ability of BT474-TR cells but not that of the parental line (BT474). This was accompanied by a reduction of Her2 protein levels and AKT phosphorylation (S473), as well as a decrease in Her2 stability, which was also observed in JIMT1 and MDA-453, naturally trastuzumab-resistant cells. In addition, ATG9A indirectly promoted c-Cbl recruitment to Her2 on T1112, a known c-Cbl docking site, leading to increased K63 Her2 polyubiquitination. Whereas silencing c-Cbl abrogated ATG9A repressive effects on Her2 and downstream PI3K/AKT signaling, its depletion restored BT474-TR proliferative rate. Taken together, our findings show for this first time that ATG9A loss in trastuzumab resistant cells allowed Her2 to escape from lysosomal targeted degradation through K63 poly-ubiquitination via c-Cbl. This study identifies ATG9A as a potentially druggable target to overcome resistance to anti-Her2 blockade.
Angelopoulos N, Stebbing J, Xu Y, et al., 2016, Proteome-wide dataset supporting functional study of tyrosine kinases in breast cancer., Data in Brief, Vol: 7, Pages: 740-746, ISSN: 2352-3409
Tyrosine kinases (TKs) play an essential role in regulating various cellular activities and dysregulation of TK signaling contributes to oncogenesis. However, less than half of the TKs have been thoroughly studied. Through a combined use of RNAi and stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomics, a global functional proteomic landscape of TKs in breast cancer was recently revealed highlighting a comprehensive and highly integrated signaling network regulated by TKs (Stebbing et al., 2015) [1]. We collate the enormous amount of the proteomic data in an open access platform, providing a valuable resource for studying the function of TKs in cancer and benefiting the science community. Here we present a detailed description related to this study (Stebbing et al., 2015) [1] and the raw data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the identifier PXD002065.
Favicchio R, Thepaut C, Zhang H, et al., 2016, Strategies in functional proteomics: Unveiling the pathways to precision oncology., Cancer Letters, ISSN: 1872-7980
Personalised strategies in cancer care are required to overcome the therapeutic challenges posed by variability between patients and disease subsets. To this end, enhanced precision tools must be developed to describe the molecular drivers of malignant proliferation. Such tools must also identify druggable targets and biomarkers in order to provide essential information regarding drug development and therapeutic outcome. Here we discuss how proteomics-based approaches provide a set of viable methodologies capable of delivering quantitative information throughout the main stages of personalised oncology and a ratiometric platform that delivers systems-wide methods for drug evaluation.
Schofield GM, Urch CE, Stebbing J, et al., 2016, Reply: When does a human being die?, QJM-AN INTERNATIONAL JOURNAL OF MEDICINE, Vol: 109, Pages: 146-146, ISSN: 1460-2725
Jacob J, Favicchio R, Karimian N, et al., 2015, LMTK3 escapes tumour suppressor miRNAs via sequestration of DDX5., Cancer Letters, Vol: 372, Pages: 137-146, ISSN: 1872-7980
Lemur tyrosine kinase-3 (LMTK3) plays an important role in cancer progression and is associated with breast, lung, gastric and colorectal cancer. MicroRNAs (miRNAs) are small endogenous non-coding RNAs that typically repress target genes at post-transcriptional level and have an important role in tumorigenesis. By performing a miRNA expression profile, we identified a subset of miRNAs modulated by LMTK3. We show that LMTK3 induces miR-34a, miR-196-a2 and miR-182 levels interacting with DEAD-box RNA helicase p68 (DDX5). LMTK3 binds via DDX5 to the pri-miRNA of these three mature miRNAs, thereby sequestrating them from further processing. Ectopic expression of miR-34a and miR-182 in LMTK3-overexpressing cell lines (MCF7-LMTK3 and MDA-MB-231-LMTK3) inhibits breast cancer proliferation, invasion and migration. Interestingly, miR-34a and miR-182 directly bind to the 3'UTR of LMTK3 mRNA and consequently inhibit both its stability and translation, acting as tumour suppressor-like miRNAs. In aggregate, we show that LMTK3 is involved in miRNA biogenesis through modulation of the Microprocessor complex, inducing miRNAs that target LMTK3 itself.
Rampias T, Favicchio R, Stebbing J, et al., 2015, Targeting tumor-stroma crosstalk: the example of the NT157 inhibitor., Oncogene, ISSN: 1476-5594
Recent clinical research has provided evidence that cancer progression and therapy resistance is driven not only by tumor's genetic profile but also by complex paracrine interactions within the tumor microenvironment (TME). The role of TME in modulating tumor drug sensitivity is increasingly recognized and targeting TME has been the focus of novel therapeutic approaches. Two recent reports show that a new anti-cancer drug, the inhibitor NT157 has the potential to inhibit IGF-1R and STAT3 signaling pathways in cancer cells and stoma cells of TME leading to a decrease in cancer cell survival.Oncogene advance online publication, 19 October 2015; doi:10.1038/onc.2015.392.
Stebbing J, Zhang H, Xu Y, et al., 2015, Characterization of the Tyrosine Kinase-Regulated Proteome in Breast Cancer by Combined use of RNA interference (RNAi) and Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC) Quantitative Proteomics, Molecular & Cellular Proteomics, Vol: 14, Pages: 2479-2492, ISSN: 1535-9484
Tyrosine kinases (TKs) are central regulators in cellular activities and perturbations of TK signaling contribute to oncogenesis. However, less than half of the TKs have been thoroughly studied and a global functional analysis of their proteomic portrait is lacking. Here we conducted a combined approach of RNA interference (RNAi) and stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomics to decode the TK-regulated proteome and associated signaling dynamics. As a result, a broad proteomic repertoire modulated by TKs was revealed, upon silencing of the 65 TKs expressed in MCF7 breast cancer cells. This yielded 10 new distinctive TK clusters according to similarity in TK-regulated proteome, each characterized by a unique signaling signature in contrast to previous classifications. We provide functional analyses and identify critical pathways for each cluster based on their common downstream targets. Analysis of different breast cancer subtypes showed distinct correlations of each cluster with clinical outcome. From the significantly up- and down-regulated proteins, we identified a number of markers of drug sensitivity and resistance. These data supports the role of TKs in regulating major aspects of cellular activity, but also reveals redundancy in signaling, explaining why kinase inhibitors alone often fail to achieve their clinical aims. The TK-SILACepedia provides a comprehensive resource for studying the global function of TKs in cancer.
Xu Y, Zhang H, Van TMN, et al., 2015, LMTK3 represses tumor suppressor-like genes through chromatin remodeling in breast cancer, Cell Reports, Vol: 12, Pages: 837-849, ISSN: 2211-1247
LMTK3 is an oncogenic receptor tyrosine kinase (RTK) implicated in various types of cancer, including breast, lung, gastric, and colorectal cancer. It is localized in different cellular compartments, but its nuclear function has not been investigated so far. We mapped LMTK3 binding across the genome using ChIP-seq and found that LMTK3 binding events are correlated with repressive chromatin markers. We further identified KRAB-associated protein 1 (KAP1) as a binding partner of LMTK3. The LMTK3/KAP1 interaction is stabilized by PP1α, which suppresses KAP1 phosphorylation specifically at LMTK3-associated chromatin regions, inducing chromatin condensation and resulting in transcriptional repression of LMTK3-bound tumor suppressor-like genes. Furthermore, LMTK3 functions at distal regions in tethering the chromatin to the nuclear periphery, resulting in H3K9me3 modification and gene silencing. In summary, we propose a model where a scaffolding function of nuclear LMTK3 promotes cancer progression through chromatin remodeling.
Schofield GM, Urch CE, Stebbing J, et al., 2015, When does a human being die?, QJM-AN INTERNATIONAL JOURNAL OF MEDICINE, Vol: 108, Pages: 605-609, ISSN: 1460-2725
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- Citations: 12
Zhang H, Angelopoulos N, Xu Y, et al., 2015, Proteomic profile of KSR1-regulated signalling in response to genotoxic agents in breast cancer, Breast Cancer Research and Treatment, Vol: 151, Pages: 555-568, ISSN: 1573-7217
Kinase suppressor of Ras 1 (KSR1) has beenimplicated in tumorigenesis in multiple cancers, includingskin, pancreatic and lung carcinomas. However, our recentstudy revealed a role of KSR1 as a tumour suppressor inbreast cancer, the expression of which is potentially correlatedwith chemotherapy response. Here, we aimed tofurther elucidate the KSR1-regulated signalling in responseto genotoxic agents in breast cancer. Stable isotope labellingby amino acids in cell culture (SILAC) coupled tohigh-resolution mass spectrometry (MS) was implementedto globally characterise cellular protein levels induced byKSR1 in the presence of doxorubicin or etoposide. Theacquired proteomic signature was compared and GOSTRINGanalysis was subsequently performed to illustratethe activated functional signalling networks. Furthermore,the clinical associations of KSR1 with identified targetsand their relevance in chemotherapy response were examinedin breast cancer patients. We reveal a comprehensiverepertoire of thousands of proteins identified ineach dataset and compare the unique proteomic profiles aswell as functional connections modulated by KSR1 afterdoxorubicin (Doxo-KSR1) or etoposide (Etop-KSR1) stimulus.From the up-regulated top hits, several proteins,including STAT1, ISG15 and TAP1 are also found to bepositively associated with KSR1 expression in patientsamples. Moreover, high KSR1 expression, as well as highabundance of these proteins, is correlated with better survivalin breast cancer patients who underwent chemotherapy.In aggregate, our data exemplify a broad functionalnetwork conferred by KSR1 with genotoxic agents andhighlight its implication in predicting chemotherapy responsein breast cancer.
Stebbing J, Zhang H, Xu Y, et al., 2015, KSR1 regulates BRCA1 degradation and inhibits breast cancer growth, ONCOGENE, Vol: 34, Pages: 2103-2114, ISSN: 0950-9232
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- Citations: 13
Papanastasopoulos P, Giamas G, 2015, mTOR inhibition in breast cancer, BREAST CANCER MANAGEMENT, Vol: 4, Pages: 67-70, ISSN: 1758-1923
Zhang H, Stebbing J, Giamas G, 2015, The many-faced KSR1: a tumor suppressor in breast cancer., Oncoscience, Vol: 2, Pages: 669-670, ISSN: 2331-4737
Zhang H, Xu Y, Papanastasopoulos P, et al., 2014, Broader implications of SILAC-based proteomics for dissecting signaling dynamics in cancer, EXPERT REVIEW OF PROTEOMICS, Vol: 11, Pages: 713-731, ISSN: 1478-9450
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- Citations: 5
Benhaim L, Zhang W, Wakatsuki T, et al., 2014, Genetic variants of kinase suppressors of Ras (KSR1) to predict survival in patients with ER alpha-positive advanced breast cancer, Pharmacogenomics Journal, Vol: 15, Pages: 235-240, ISSN: 1473-1150
In patients with breast cancer (BC), deregulation of estrogen receptor (ERα) activity may account for most resistance to endocrine therapies. Our previous study used a whole-human kinome siRNA screen to identify functional actors in ERα modulation and showed the implication of proteins kinase suppressors of ras (KSR1). From those findings we evaluated the clinical impact of KSR1 variants in patients with ERα+ BC treated with TAM. DNA was obtained from 222 patients with advanced ERα+ BC treated with TAM who had undergone surgery from 1981 to 2003. We selected three potentially functional relevant KSR1 polymorphisms; two within the 3’UTR (rs224190, rs1075952) and one in the coding exon 7 (rs2293180). The primary end points were overall survival (OS) and disease-free survival (DFS). After a 6.4-year median follow-up, patients carrying the rs2241906 TT genotype showed shorter DFS (2.1 vs 7.1 years, P=0.005) and OS (2.6 vs 8.4 years P=0.002) than those with the TC or TT genotypes. Those associations remained significant in the multivariable analysis adjusting age, lymph node status, LMTK3 and IGFR variants and HER2 status. The polymorphisms rs2241906 and rs1075952 were in linkage disequilibrium. No association was shown between rs2293180 and survival. Among the actors of ERα signaling, KSR1 rs2241906 variants may predict survival in patients with advanced ERα+ BC treated with adjuvant TAM.
Zhang H, Stebbing J, Xu Y, et al., 2014, Global mapping of tyrosine kinase signalling in breast cancer by combined use of RNAi and SILAC quantitative proteomics, 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Magturo S, Giamas G, Mallick S, et al., 2014, Evaluation of LMTK3 expression and tumor phenotype in estrogen-dependent colorectal cancer, 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Mazarakis NK, Smith S, Vraka A, et al., 2014, The expression of lemur tyrosine kinase-3 in high grade pediatric tumors, 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Nunes JFG, Zhang H, Stebbing J, et al., 2014, SILAC-BASED ANALYSIS REVEALS A UNIQUE PHOSPHOPROTEOMIC-SIGNATURE OF HER2-RESISTANT BREAST CANCER CELLS, ANTICANCER RESEARCH, Vol: 34, Pages: 5900-5900, ISSN: 0250-7005
Xu Y, Zhang H, Vorgias C, et al., 2014, POSITIONING LMTK3 ON THE MAP OF ONCOGENIC SIGNALING CASCADES AND ELUCIDATING ITS ROLE IN INVASION AND METASTASIS IN BREAST CANCER, ANTICANCER RESEARCH, Vol: 34, Pages: 5923-5924, ISSN: 0250-7005
Xu Y, Zhang H, Giamas G, 2014, Targeting lemurs against cancer metastasis, ONCOTARGET, Vol: 5, Pages: 5192-5193
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- Citations: 5
Xu Y, Zhang H, Lit LC, et al., 2014, The Kinase LMTK3 Promotes Invasion in Breast Cancer Through GRB2-Mediated Induction of Integrin β<sub>1</sub>, SCIENCE SIGNALING, Vol: 7, ISSN: 1945-0877
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- Citations: 31
Stebbing J, Lit LC, Zhang H, et al., 2014, The regulatory roles of phosphatases in cancer, ONCOGENE, Vol: 33, Pages: 939-953, ISSN: 0950-9232
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- Citations: 77
Winder T, Giamas G, Wilson PM, et al., 2014, Insulin-like growth factor receptor polymorphism defines clinical outcome in estrogen receptor-positive breast cancer patients treated with tamoxifen, PHARMACOGENOMICS JOURNAL, Vol: 14, Pages: 28-34, ISSN: 1470-269X
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- Citations: 26
Melaiu O, Stebbing J, Lombardo Y, et al., 2014, <i>MSLN</i> Gene Silencing Has an Anti-Malignant Effect on Cell Lines Overexpressing Mesothelin Deriving from Malignant Pleural Mesothelioma, PLOS ONE, Vol: 9, ISSN: 1932-6203
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- Citations: 22
Zhang H, Xu Y, Filipovic A, et al., 2013, SILAC-based phosphoproteomics reveals an inhibitory role of KSR1 in p53 transcriptional activity via modulation of DBC1, British Journal of Cancer, Vol: 109, Pages: 2675-2684, ISSN: 1532-1827
Background: We have previously identified kinase suppressor of ras-1 (KSR1) as a potential regulatory gene in breast cancer.KSR1, originally described as a novel protein kinase, has a role in activation of mitogen-activated protein kinases. Emergingevidence has shown that KSR1 may have dual functions as an active kinase as well as a scaffold facilitating multiprotein complexassembly. Although efforts have been made to study the role of KSR1 in certain tumour types, its involvement in breast cancerremains unknown.Methods: A quantitative mass spectrometry analysis using stable isotope labelling of amino acids in cell culture (SILAC) wasimplemented to identify KSR1-regulated phosphoproteins in breast cancer. In vitro luciferase assays, co-immunoprecipitation aswell as western blotting experiments were performed to further study the function of KSR1 in breast cancer.Results: Of significance, proteomic analysis reveals that KSR1 overexpression decreases deleted in breast cancer-1 (DBC1)phosphorylation. Furthermore, we show that KSR1 decreases the transcriptional activity of p53 by reducing the phosphorylation ofDBC1, which leads to a reduced interaction of DBC1 with sirtuin-1 (SIRT1); this in turn enables SIRT1 to deacetylate p53.Conclusion: Our findings integrate KSR1 into a network involving DBC1 and SIRT1, which results in the regulation of p53acetylation and its transcriptional activity
Stebbing J, Filipovic A, Giamas G, 2013, Claudin-1 as a promoter of EMT in hepatocellular carcinoma, ONCOGENE, Vol: 32, Pages: 4871-4872, ISSN: 0950-9232
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- Citations: 32
Wakatsuki T, LaBonte MJ, Bohanes PO, et al., 2013, Prognostic Role of Lemur Tyrosine Kinase-3 Germline Polymorphisms in Adjuvant Gastric Cancer in Japan and the United States, MOLECULAR CANCER THERAPEUTICS, Vol: 12, Pages: 2261-2272, ISSN: 1535-7163
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- Citations: 16
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