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

105 results found

Lane R, Cilibrasi C, Chen J, Shah K, Messuti E, Mazarakis NK, Stebbing J, Critchley G, Song E, Simon T, Giamas Get al., 2022, PDGF-R inhibition induces glioblastoma cell differentiation via DUSP1/p38(MAPK) signalling, ONCOGENE, Vol: 41, Pages: 2749-2763, ISSN: 0950-9232

Journal article

Wang Z, Zhu L, Li K, Sun Y, Giamas G, Stebbing J, Peng L, Yu Zet al., 2022, Alternative splicing events in tumor immune infiltration in renal clear cell carcinomas, CANCER GENE THERAPY, ISSN: 0929-1903

Journal article

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 MJ, Pardo Eet al., 2022, Re: Repurposed Floxacins Targeting RSK4 Prevent Chemoresistance and Metastasis in Lung and Bladder Cancer, JOURNAL OF UROLOGY, Vol: 207, Pages: 919-920, ISSN: 0022-5347

Journal article

Zhu L, Wang Z, Sun Y, Giamas G, Stebbing J, Yu Z, Peng Let al., 2021, A Prediction Model Using Alternative Splicing Events and the Immune Microenvironment Signature in Lung Adenocarcinoma, FRONTIERS IN ONCOLOGY, Vol: 11, ISSN: 2234-943X

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, Vol: 74, Pages: 2561-2579, 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

Peng L, Li J, Wu J, Xu B, Wang Z, Giamas G, Stebbing J, Yu Zet al., 2021, A Pan-Cancer Analysis of SMARCA4 Alterations in Human Cancers, FRONTIERS IN IMMUNOLOGY, Vol: 12, ISSN: 1664-3224

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

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

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, COMMUNICATIONS BIOLOGY, Vol: 2

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

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

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, Abstract 1775: Targeting RSK4 prevents both chemoresistance and metastasis in lung cancer, AACR Annual Meeting on Bioinformatics, Convergence Science, and Systems Biology, Publisher: American Association for Cancer Research, Pages: 1-2, ISSN: 0008-5472

Lung cancer is the commonest cause of cancer death worldwide with a five-year survival rate of less than five percent for metastatic tumors. Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancer cases of which adenocarcinoma prevails. Patients almost invariably develop metastatic drug-resistant disease and this is responsible for our failure to provide curative therapy. Hence, a better understanding of the mechanisms underlying these biological processes is urgently required to improve clinical outcome.The 90-kDa ribosomal S6 kinases (RSKs) are downstream effectors of the RAS/MAPK cascade. RSKs are highly conserved serine/threonine protein kinases implicated in diverse cellular processes, including cell survival, proliferation, migration and invasion. Four isoforms exist in humans (RSK1-4) and are uniquely characterized by the presence of two non-identical N- and C-terminal kinase domains. RSK isoforms are 73-80% identical at protein level and this has been thought to suggest overlapping functions.However, through functional genomic kinome screens, we show that RSK4, contrary to RSK1, promotes both drug resistance and metastasis in lung cancer. This kinase is overexpressed in the majority (57%) of NSCLC biopsies and this correlates with poor overall survival in lung adenocarcinoma patients. Genetic silencing of RSK4 sensitizes lung cancer cells to chemotherapy and prevents their migration and invasiveness in vitro and in vivo. RSK4 downregulation decreases the anti-apoptotic proteins Bcl2 and cIAP1/2 which correlates with increased apoptotic signalling, whilst it also induces mesenchymal-epithelial transition (MET) through inhibition of NFκB activity. A small-molecule inhibitor screen identified several floxacins, including trovafloxacin, as potent allosteric inhibitors of RSK4 activation. Trovafloxacin reproduced all biological and molecular effects of RSK4 silencing in vitro and in vivo, and is predicted to bind a novel allosteric site revealed

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

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