Imperial College London

DrGeorgiosGiamas

Faculty of MedicineDepartment of Surgery & Cancer

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 7594 2804g.giamas Website

 
 
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Location

 

Hammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

100 results found

Wendler F, Purice T-M, Simon T, Stebbing J, Giamas Get al., 2021, The LMTK-family of kinases: Emerging important players in cell physiology and pathogenesis, BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, Vol: 1867, ISSN: 0925-4439

Journal article

Pardo O, Chrysostomou S, Roy R, Prischi F, Thamlikitkul L, Chapman KL, Mufti U, Peach R, Ding L, Hancock D, Moore C, Molina-Arcas M, Mauri F, Pinato DJ, Abrahams JM, Ottaviani S, Castellano L, Giamas G, Pascoe J, Moonamale D, Pirrie S, Gaunt C, Billingham L, Steven NM, Cullen M, Hrouda D, Winkler M, Post J, Cohen P, Salpeter SJ, Bar V, Zundelevich A, Golan S, Leibovici D, Lara R, Klug DR, Yaliraki SN, Barahona M, Wang Y, Downward J, Skehel JM, Ali MMU, Seckl MJet al., 2021, Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer, Science Translational Medicine, Vol: 13, ISSN: 1946-6234

Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4’s hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased (P = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.

Journal article

Lepore A, Choy PM, Lee NC, Carella MA, Favicchio R, Briones-Orta MA, Glaser SS, Alpini G, D'Santos C, Tooze RM, Lorger M, Syn W-K, Papakyriakou A, Giamas G, Bubici C, Papa Set al., 2021, Phosphorylation and stabilization of PIN1 by JNK promote intrahepatic cholangiocarcinoma growth, Hepatology, ISSN: 0270-9139

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive type of liver cancer in urgent need of treatment options. Aberrant activation of c-Jun N-terminal kinase (JNK) pathway is a key feature in ICC and an attractive candidate target for its treatment. However, the mechanisms by which constitutive JNK activation promotes ICC growth, and thus the key downstream effectors of this pathway remain unknown for their applicability as therapeutic targets. Our aim was to obtain a better mechanistic understanding of the role of JNK signalling in ICC that could open new therapeutic opportunities. APPROACH AND RESULTS: Using loss- and gain-of-function studies in vitro and in vivo, we show that activation of the JNK pathway promotes ICC cell proliferation by affecting the protein stability of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), a key driver of tumorigenesis. PIN1 is highly expressed in ICC primary tumours, and its expression positively correlates with active JNK. Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation. Moreover, pharmacological inhibition of PIN1 via all-trans retinoic acid (ATRA), an FDA-approved drug, impairs the growth of both cultured and xenografted ICC cells. CONCLUSIONS: Our findings implicate the JNK-PIN1 regulatory axis as a functionally important determinant for ICC growth, and provide a rationale for therapeutic targeting of JNK activation via PIN1 inhibition.

Journal article

Stebbing J, Zhang H, Xu Y, Lit LC, Green AR, Grothey A, Lombardo Y, Periyasamy M, Blighe K, Zhang W, Shaw JA, Ellis IO, Lenz HJ, Giamas Get al., 2021, KSR1 regulates BRCA1 degradation and inhibits breast cancer growth (vol 34, pg 2103, 2015), ONCOGENE, ISSN: 0950-9232

Journal article

Stebbing J, Zhang H, Xu Y, Lit LC, Green AR, Grothey A, Lombardo Y, Periyasamy M, Blighe K, Zhang W, Shaw JA, Ellis IO, Lenz HJ, Giamas Get al., 2021, KSR1 regulates BRCA1 degradation and inhibits breast cancer growth (vol 31, pg 2103, 2015), ONCOGENE, Vol: 40, Pages: 3473-3473, ISSN: 0950-9232

Journal article

Cilibrasi C, Ditsiou A, Papakyriakou A, Mavridis G, Eravci M, Stebbing J, Gagliano T, Giamas Get al., 2021, LMTK3 inhibition affects microtubule Stability (vol 20, 53, 2021), MOLECULAR CANCER, Vol: 20

Journal article

Cilibrasi C, Ditsiou A, Papakyriakou A, Mavridis G, Eravci M, Stebbing J, Gagliano T, Giamas Get al., 2021, LMTK3 inhibition affects microtubule stability, Molecular Cancer, Vol: 20, Pages: 1-6, ISSN: 1476-4598

Journal article

Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, Abeliovich H, Abildgaard MH, Abudu YP, Acevedo-Arozena A, Adamopoulos IE, Adeli K, Adolph TE, Adornetto A, Aflaki E, Agam G, Agarwal A, Aggarwal BB, Agnello M, Agostinis P, Agrewala JN, Agrotis A, Aguilar P, Ahmad ST, Ahmed ZM, Ahumada-Castro U, Aits S, Aizawa S, Akkoc Y, Akoumianaki T, Akpinar HA, Al-Abd AM, Al-Akra L, Al-Gharaibeh A, Alaoui-Jamali MA, Alberti S, Alcocer-Gomez E, Alessandri C, Ali M, Al-Bari MAA, Aliwaini S, Alizadeh J, Almacellas E, Almasan A, Alonso A, Alonso GD, Altan-Bonnet N, Altieri DC, Alves S, da Costa CA, Alzaharna MM, Amadio M, Amantini C, Amaral C, Ambrosio S, Amer AO, Ammanathan V, An Z, Andersen SU, Andrabi SA, Andrade-Silva M, Andres AM, Angelini S, Ann D, Anozie UC, Ansari MY, Antas P, Antebi A, Anton Z, Anwar T, Apetoh L, Apostolova N, Araki T, Araki Y, Arasaki K, Araujo WL, Araya J, Arden C, Arevalo M-A, Arguelles S, Arias E, Arikkath J, Arimoto H, Ariosa AR, Armstrong-James D, Arnaune-Pelloquin L, Aroca A, Arroyo DS, Arsov I, Artero R, Asaro DML, Aschner M, Ashrafizadeh M, Ashur-Fabian O, Atanasov AG, Au AK, Auberger P, Auner HW, Aurelian L, Autelli R, Avagliano L, Avalos Y, Aveic S, Aveleira CA, AvinWittenberg T, Aydin Y, Ayton S, Ayyadevara S, Azzopardi M, Baba M, Backer JM, Backues SK, Bae D-H, Bae O-N, Bae SH, Baehrecke EH, Baek A, Baek S-H, Baek SH, Bagetta G, Bagniewska-Zadworna A, Bai H, Bai J, Bai X, Bai Y, Bairagi N, Baksi S, Balbi T, Baldari CT, Balduini W, Ballabio A, Ballester M, Balazadeh S, Balzan R, Bandopadhyay R, Banerjee S, Banerjee S, Bao Y, Baptista MS, Baracca A, Barbati C, Bargiela A, Barila D, Barlow PG, Barmada SJ, Barreiro E, Barreto GE, Bartek J, Bartel B, Bartolome A, Barve GR, Basagoudanavar SH, Bassham DC, Jr RCB, Basu A, Batoko H, Batten I, Baulieu EE, Baumgarner BL, Bayry J, Beale R, Beau I, Beaumatin F, Bechara LRG, Beck GR, Beers MF, Begun J, Behrends C, Behrens GMN, Bei R, Bejarano E, Bel S, Behl C, Belaid A, Belgareh-Touzeet al., 2021, Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition), Autophagy, Vol: 17, Pages: 1-382, ISSN: 1554-8627

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Journal article

Ditsiou A, Cilibrasi C, Simigdala N, Papakyriakou A, Milton-Harris L, Vella V, Nettleship JE, Lo JH, Soni S, Smbatyan G, Ntavelou P, Gagliano T, Iachini MC, Khurshid S, Simon T, Zhou L, Hassell-Hart S, Carter P, Pearl LH, Owen RL, Owens RJ, Roe SM, Chayen NE, Lenz H-J, Spencer J, Prodromou C, Klinakis A, Stebbing J, Giamas Get al., 2020, The structure-function relationship of oncogenic LMTK3, SCIENCE ADVANCES, Vol: 6, ISSN: 2375-2548

Journal article

Gagliano T, Shah K, Gargani S, Lao L, Alsaleem M, Chen J, Ntafis V, Huang P, Ditsiou A, Vella V, Yadav K, Bienkowska K, Bresciani G, Kang K, Li L, Carter P, Benstead-Hume G, O'Hanlon T, Dean M, Pearl FM, Lee SC, Rakha EA, Green AR, Kontoyiannis DL, Song E, Stebbing J, Giamas Get al., 2020, PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression, Journal of Clinical Investigation, Vol: 130, Pages: 3188-3204, ISSN: 0021-9738

As there is growing evidence for the tumor microenvironment's (TME) role in tumorigenesis, we investigated the role of fibroblast-expressed kinases in triple negative breast cancer (TNBC). Using a high-throughput kinome screen combined with 3D invasion assays, we identified fibroblast-expressed PIK3Cδ (f-PIK3Cδ) as a key regulator of progression. Although PIK3Cδ was expressed in primary fibroblasts derived from TNBC patients, it was undetectable in breast cancer cell lines. Genetic and pharmacologic gain- and loss-of functions experiments verified the contribution of f-PIK3Cδ in TNBC cell invasion. Integrated secretomics and transcriptomics analyses revealed a paracrine mechanism via which f-PIK3Cδ confers its pro-tumorigenic effects. Inhibition of f-PIK3Cδ promoted the secretion of factors, including PLGF and BDNF, which led to upregulation of NR4A1 in TNBC cells where it acts as a tumor suppressor. Inhibition of PIK3Cδ in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3Cδ in cancer progression. Similar results were observed in the MMTV-PyMT transgenic BC mouse model, along with a decrease on tumor metastasis emphasizing the potential immune-independent effects of PIK3Cδ inhibition. Finally, analysis of BC patient cohorts and TCGA datasets identified f-PIK3Cδ (protein and mRNA levels) as an independent prognostic factor for overall and disease free survival, highlighting it as a therapeutic target for TNBC.

Journal article

Gagliano T, Shah K, Gargani S, Lao L, Alsaleem M, Chen J, Ntafis V, Huang P, Ditsiou A, Vella V, Yadav K, Bienkowska K, Bresciani G, Kang K, Li L, Carter P, Benstead-Hum G, OHanlon T, Dean M, Pearl FMG, Lee S-C, Rakha EA, Green AR, Kontoyiannis DL, Song E, Stebbing J, Giamas Get al., 2019, Global kinome silencing combined with 3D invasion screening of the tumor microenvironment identifies fibroblast-expressed PIK3Cδ involvement in triple-negative breast cancer progression

<jats:title>Abstract</jats:title><jats:p>As there is growing evidence for the tumor microenvironment’s (TME) role in tumorigenesis, we sought to investigate the role of fibroblast-expressed kinases in triple negative breast cancer (TNBC). Using a high-throughput kinome screen combined with 3D invasion assays, we identified fibroblast-expressed PIK3Cδ (f-PIK3Cδ) as a key regulator of progression. Although PIK3Cδ has been mainly described in leucocytes, we detected high expression in primary fibroblasts derived from TNBC patients, while PIK3Cδ was undetectable in cancer epithelial cell lines. Genetic and pharmacologic gain- and loss-of functions experiments verified the contribution of f-PIK3Cδ in TNBC cell invasion. By employing an integrated secretomics and transcriptomics analysis, we revealed a paracrine mechanism via which f-PIK3Cδ confers its pro-tumorigenic effects. Inhibition of f-PIK3Cδ promoted the secretion of factors, including PLGF and BDNF, which subsequently led to upregulation of NR4A1 in TNBC cells where it acts as a tumor suppressor. Inhibition of PIK3Cδ in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3Cδ in cancer progression. Similar results were observed in the MMTV-PyMT transgenic BC mouse model, in addition to a decrease on tumor metastasis emphasizing the potential immune-independent effects of PIK3Cδ inhibition. Finally, analysis of BC patient cohorts and TCGA datasets identified f-PIK3Cδ (protein and mRNA levels) as an independent prognostic factor for overall and disease free survival, highlighting it as a therapeutic target for TNBC.</jats:p>

Journal article

Lane R, Simon T, Vintu M, Solkin B, Koch B, Stewart N, Benstead-Hume G, Pearl FMG, Critchley G, Stebbing J, Giamas Get al., 2019, Cell-derived extracellular vesicles can be used as a biomarker reservoir for glioblastoma tumor subtyping., Commun Biol, Vol: 2

Glioblastoma (GBM) is one of the most aggressive solid tumors for which treatment options and biomarkers are limited. Small extracellular vesicles (sEVs) produced by both GBM and stromal cells are central in the inter-cellular communication that is taking place in the tumor bulk. As tumor sEVs are accessible in biofluids, recent reports have suggested that sEVs contain valuable biomarkers for GBM patient diagnosis and follow-up. The aim of the current study was to describe the protein content of sEVs produced by different GBM cell lines and patient-derived stem cells. Our results reveal that the content of the sEVs mirrors the phenotypic signature of the respective GBM cells, leading to the description of potential informative sEV-associated biomarkers for GBM subtyping, such as CD44. Overall, these data could assist future GBM in vitro studies and provide insights for the development of new diagnostic and therapeutic methods as well as personalized treatment strategies.

Journal article

Lane R, Simon T, Vintu M, Solkin B, Koch B, Stewart N, Benstead-Hume G, Pearl FMG, Critchley G, Stebbing J, Giamas Get al., 2019, Cell-derived extracellular vesicles can be used as a biomarker reservoir for glioblastoma tumor subtyping, COMMUNICATIONS BIOLOGY, Vol: 2

Journal article

Chrysostomou S, Roy R, Prischi F, Chapman K, Mufti U, Mauri F, Bellezza G, Abrahams J, Ottaviani S, Castellano L, Giamas G, Hrouda D, Winkler M, Klug D, Yaliraki S, Barahona M, Wang Y, Ali M, Seckl M, Pardo Oet al., 2019, Targeting RSK4 prevents both chemoresistance and metastasis in lung cancer, AACR Annual Meeting on Bioinformatics, Convergence Science, and Systems Biology, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

Prischi F, Chrysostomou S, Roy R, Chapman K, Mufti U, Peach R, Ding L, Mauri F, Bellezza G, Cagini L, Barbareschi M, Ferrero S, Abrahams J, Ottaviani S, Castellano L, Giamas G, Pascoe J, Moonamale D, Billingham L, Cullen M, Hrouda D, Winkler M, Klug D, Yaliraki S, Barahona M, Wang Y, Ali M, Seckl M, Pardo Oet al., 2019, Targeting RSK4 prevents both chemoresistance and metastasis in lung and bladder cancer, FEBS Open Bio, Publisher: WILEY, Pages: 330-330, ISSN: 2211-5463

Conference paper

Rani A, Stebbing J, Giamas G, Murphy Jet al., 2019, Endocrine Resistance in Hormone Receptor Positive Breast Cancer-From Mechanism to Therapy, FRONTIERS IN ENDOCRINOLOGY, Vol: 10, ISSN: 1664-2392

Journal article

Simon T, Pinioti S, Schellenberger P, Rajeeve V, Wendler F, Cutillas PR, King A, Stebbing J, Giamas Get al., 2018, Shedding of bevacizumab in tumour cells-derived extracellular vesicles as a new therapeutic escape mechanism in glioblastoma, Molecular Cancer, Vol: 17, ISSN: 1476-4598

Glioblastoma (GBM) is the most aggressive type of primary brain tumours. Anti-angiogenic therapies (AAT), such as bevacizumab, have been developed to target the tumour blood supply. However, GBM presents mechanisms of escape from AAT activity, including a speculated direct effect of AAT on GBM cells. Furthermore, bevacizumab can alter the intercellular communication of GBM cells with their direct microenvironment. Extracellular vesicles (EVs) have been recently described as main acts in the GBM microenvironment, allowing tumour and stromal cells to exchange genetic and proteomic material. Herein, we examined and described the alterations in the EVs produced by GBM cells following bevacizumab treatment. Interestingly, bevacizumab that is able to neutralise GBM cells-derived VEGF-A, was found to be directly captured by GBM cells and eventually sorted at the surface of the respective EVs. We also identified early endosomes as potential pathways involved in the bevacizumab internalisation by GBM cells. Via MS analysis, we observed that treatment with bevacizumab induces changes in the EVs proteomic content, which are associated with tumour progression and therapeutic resistance. Accordingly, inhibition of EVs production by GBM cells improved the anti-tumour effect of bevacizumab. Together, this data suggests of a potential new mechanism of GBM escape from bevacizumab activity.

Journal article

Stebbing J, Shah K, Lit LC, Gagliano T, Ditsiou A, Wang T, Wendler F, Simon T, Szabó KS, O'Hanlon T, Dean M, Roslani AC, Cheah SH, Lee S-C, Giamas Get al., 2018, LMTK3 confers chemo-resistance in breast cancer, Oncogene, Vol: 37, Pages: 3113-3130, ISSN: 0950-9232

Lemur tyrosine kinase 3 (LMTK3) is an oncogenic kinase that is involved in different types of cancer (breast, lung, gastric, colorectal) and biological processes including proliferation, invasion, migration, chromatin remodeling as well as innate and acquired endocrine resistance. However, the role of LMTK3 in response to cytotoxic chemotherapy has not been investigated thus far. Using both 2D and 3D tissue culture models, we found that overexpression of LMTK3 decreased the sensitivity of breast cancer cell lines to cytotoxic (doxorubicin) treatment. In a mouse model we showed that ectopic overexpression of LMTK3 decreases the efficacy of doxorubicin in reducing tumor growth. Interestingly, breast cancer cells overexpressing LMTK3 delayed the generation of double strand breaks (DSBs) after exposure to doxorubicin, as measured by the formation of γH2AX foci. This effect was at least partly mediated by decreased activity of ataxia-telangiectasia mutated kinase (ATM) as indicated by its reduced phosphorylation levels. In addition, our RNA-seq analyses showed that doxorubicin differentially regulated the expression of over 700 genes depending on LMTK3 protein expression levels. Furthermore, these genes were found to promote DNA repair, cell viability and tumorigenesis processes / pathways in LMTK3-overexpressing MCF7 cells. In human cancers, immunohistochemistry staining of LMTK3 in pre- and post-chemotherapy breast tumor pairs from four separate clinical cohorts revealed a significant increase of LMTK3 following both doxorubicin and docetaxel based chemotherapy. In aggregate, our findings show for the first time a contribution of LMTK3 in cytotoxic drug resistance in breast cancer.

Journal article

Wendler F, Favicchio R, Simon T, Alifrangis C, Stebbing J, Giamas Get al., 2017, Extracellular vesicles swarm the cancer microenvironment: from tumor-stroma communication to drug intervention, ONCOGENE, Vol: 36, Pages: 877-884, ISSN: 0950-9232

Journal article

Melaiu O, Stebbing J, Lombardo Y, Bracci E, Uehara N, Bonotti A, Cristaudo A, Foddis R, Mutti L, Barale R, Gemignani F, Giamas G, Landi Set al., 2017, MSLN gene silencing has an anti-malignant effect on cell lines overexpressing mesothelin deriving from malignant pleural mesothelioma (vol 9, e85935, 2014), PLoS ONE, Vol: 12, ISSN: 1932-6203

Journal article

Giamas G, Grothey T, Grothey A, Stebbing Jet al., 2017, Stromal kinome screening identifies a novel regulatory kinase implicated in fibroblast-mediated progression of invasion in triple negative breast cancer tumours, San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

Angelopoulos N, Abdallah S, Giamas G, 2016, Advances in integrative statistics for logic programming, INTERNATIONAL JOURNAL OF APPROXIMATE REASONING, Vol: 78, Pages: 103-115, ISSN: 0888-613X

Journal article

Lucchiari G, Zhang H, Nunes J, Xu Y, Grothey A, Stebbing J, Giamas Get 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

Conference paper

Favicchio R, Angelopoulos N, Brickute D, Fortt R, Twyman F, Giamas G, Lacal JC, Aboagye EOet al., 2016, Choline metabolism is an early predictor of EGFR-mediated survival in NSCLC, AACR 107th Annual Meeting on Bioinformatics and Systems Biology, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

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

Journal article

Nunes J, Zhang H, Angelopoulos N, Chhetri J, Osipo C, Grothey A, Stebbing J, Giamas Get 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.

Journal article

Angelopoulos N, Stebbing J, Xu Y, Giamas G, Zhang Het 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.

Journal article

Favicchio R, Thepaut C, Zhang H, Arends R, Stebbing J, Giamas Get 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.

Journal article

Schofield GM, Urch CE, Stebbing J, Giamas Get al., 2016, Reply: When does a human being die?, QJM-AN INTERNATIONAL JOURNAL OF MEDICINE, Vol: 109, Pages: 146-146, ISSN: 1460-2725

Journal article

Jacob J, Favicchio R, Karimian N, Mehrabi M, Harding V, Castellano L, Stebbing J, Giamas Get 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.

Journal article

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