Imperial College London

ProfessorEricLam

Faculty of MedicineDepartment of Surgery & Cancer

Professor of Molecular Oncology
 
 
 
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Contact

 

+44 (0)20 7594 2810eric.lam

 
 
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Location

 

134ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

256 results found

Yao S, Mahmud Z, Sachini N, Aimjongjun S, Saavedra-García P, Lam EW-Fet al., 2019, Characterization of FOXO Acetylation., Methods Mol Biol, Vol: 1890, Pages: 77-90

FOXO3 is a tumor suppressor that orchestrates the expression of genes that regulate cell cycle progression, apoptosis, metabolism, oxidative stress, and other important cellular processes. Its inactivation is closely associated with tumorigenesis and cancer progression. On the other hand, sirtuin proteins have been demonstrated to be able to deacetylate, thus causing FOXO3 inactivation at the posttranslational level. Therefore, targeting sirtuin proteins renders new avenues for breast cancer treatment. Here, we describe three procedures for studying FOXO3 posttranslational modifications controlled by sirtuin proteins in cancer cells.

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Intuyod K, Saavedra-García P, Zona S, Lai C-F, Jiramongkol Y, Vaeteewoottacharn K, Pairojkul C, Yao S, Yong J-S, Trakansuebkul S, Waraasawapati S, Luvira V, Wongkham S, Pinlaor S, Lam EW-Fet al., 2018, FOXM1 modulates 5-fluorouracil sensitivity in cholangiocarcinoma through thymidylate synthase (TYMS): implications of FOXM1-TYMS axis uncoupling in 5-FU resistance., Cell Death Dis, Vol: 9

Fluorouracil (5-FU) is the first-line chemotherapeutic drug for cholangiocarcinoma (CCA), but its efficacy has been compromised by the development of resistance. Development of 5-FU resistance is associated with elevated expression of its cellular target, thymidylate synthase (TYMS). E2F1 transcription factor has previously been shown to modulate the expression of FOXM1 and TYMS. Immunohistochemical (IHC) analysis revealed a strong correlated upregulation of FOXM1 (78%) and TYMS (48%) expression at the protein levels in CCA tissues. In agreement, RT-qPCR and western blot analyses of four human CCA cell lines at the baseline level and in response to high doses of 5-FU revealed good correlations between FOXM1 and TYMS expression in the CCA cell lines tested, except for the highly 5-FU-resistant HuCCA cells. Consistently, siRNA-mediated knockdown of FOXM1 reduced the clonogenicity and TYMS expression in the relatively sensitive KKU-D131 but not in the highly resistant HuCCA cells. Interestingly, silencing of TYMS sensitized both KKU-D131 and HuCCA to 5-FU treatment, suggesting that resistance to very high levels of 5-FU is due to the inability of the genotoxic sensor FOXM1 to modulate TYMS expression. Consistently, ChIP analysis revealed that FOXM1 binds efficiently to the TYMS promoter and modulates TYMS expression at the promoter level upon 5-FU treatment in KKU-D131 but not in HuCCA cells. In addition, E2F1 expression did not correlate with either FOXM1 or TYMS expression and E2F1 depletion has no effects on the clonogenicity and TYMS expression in the CCA cells. In conclusion, our data show that FOXM1 regulates TYMS expression to modulate 5-FU resistance in CCA and that severe 5-FU resistance can be caused by the uncoupling of the regulation of TYMS by FOXM1. Our findings suggest that the FOXM1-TYMS axis can be a novel diagnostic, predictive and prognostic marker as well as a therapeutic target for CCA.

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Vervoort SJ, de Jong OG, Roukens MG, Frederiks CL, Vermeulen JF, Lourenço AR, Bella L, Vidakovic AT, Sandoval JL, Moelans C, van Amersfoort M, Dallman MJ, Bruna A, Caldas C, Nieuwenhuis E, van der Wall E, Derksen P, van Diest P, Verhaar MC, Lam EW-F, Mokry M, Coffer PJet al., 2018, Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis., Elife, Vol: 7

The expression of the transcription factor SOX4 is increased in many human cancers, however, the pro-oncogenic capacity of SOX4 can vary greatly depending on the type of tumor. Both the contextual nature and the mechanisms underlying the pro-oncogenic SOX4 response remain unexplored. Here, we demonstrate that in mammary tumorigenesis, the SOX4 transcriptional network is dictated by the epigenome and is enriched for pro-angiogenic processes. We show that SOX4 directly regulates endothelin-1 (ET-1) expression and can thereby promote tumor-induced angiogenesis both in vitro and in vivo. Furthermore, in breast tumors, SOX4 expression correlates with blood vessel density and size, and predicts poor-prognosis in patients with breast cancer. Our data provide novel mechanistic insights into context-dependent SOX4 target gene selection, and uncover a novel pro-oncogenic role for this transcription factor in promoting tumor-induced angiogenesis. These findings establish a key role for SOX4 in promoting metastasis through exploiting diverse pro-tumorigenic pathways.

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Zhang B, Lam EW-F, Sun Y, 2018, Senescent cells: A new Achilles' heel to exploit for cancer medicine?, Aging Cell

Cellular senescence is a typical tumor-suppressive mechanism that restricts the proliferation of premalignant cells. However, mounting evidence suggests that senescent cells, which also persist in vivo, can promote the incidence of aging-related disorders principally via the senescence-associated secretory phenotype (SASP), among which cancer is particularly devastating. Despite the beneficial effects of the SASP on certain physiological events such as wound healing and tissue repair, more studies have demonstrated that senescent cells can substantially contribute to pathological conditions and accelerate disease exacerbation, particularly cancer resistance, relapse and metastasis. To limit the detrimental properties while retaining the beneficial aspects of senescent cells, research advancements that support screening, design and optimization of anti-aging therapeutic agents are in rapid progress in the setting of prospective development of clinical strategies, which together represent a new wave of efforts to control human malignancies or mitigate degenerative complications.

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Li M, Chai H-F, Peng F, Meng Y-T, Zhang L-Z, Zhang L, Zou H, Liang Q-L, Li M-M, Mao K-G, Sun D-X, Tong M-Y, Deng Z-Q, Hou Z-J, Zhao Y, Li J, Wang X-C, Lv S-S, Zhang Q-Q, Yu X, Lam EW-F, Liu Q, Cui X-N, Xu Jet al., 2018, Estrogen receptor beta upregulated by lncRNA-H19 to promote cancer stem-like properties in papillary thyroid carcinoma, CELL DEATH & DISEASE, Vol: 9, ISSN: 2041-4889

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Wahba J, Natoli M, Whilding LM, Parente-Pereira AC, Jung Y, Zona S, Lam EW-F, Smith JR, Maher J, Ghaem-Maghami Set al., 2018, Chemotherapy-induced apoptosis, autophagy and cell cycle arrest are key drivers of synergy in chemo-immunotherapy of epithelial ovarian cancer, CANCER IMMUNOLOGY IMMUNOTHERAPY, Vol: 67, Pages: 1753-1765, ISSN: 0340-7004

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Phoomak C, Silsirivanit A, Park D, Sawanyawisuth K, Vaeteewoottacharn K, Wongkham C, Lam EW-F, Pairojkul C, Lebrilla CB, Wongkham Set al., 2018, O-GlcNAcylation mediates metastasis of cholangiocarcinoma through FOXO3 and MAN1A1, ONCOGENE, Vol: 37, Pages: 5648-5665, ISSN: 0950-9232

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Chen F, Long Q, Fu D, Zhu D, Ji Y, Han L, Zhang B, Xu Q, Liu B, Li Y, Wu S, Yang C, Qian M, Xu J, Liu S, Cao L, Chin YE, Lam EW-F, Coppe J-P, Sun Yet al., 2018, Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance, NATURE COMMUNICATIONS, Vol: 9, ISSN: 2041-1723

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Sun Y, Coppe J-P, Lam EW-F, 2018, Cellular Senescence: The Sought or the Unwanted?, TRENDS IN MOLECULAR MEDICINE, Vol: 24, Pages: 871-885, ISSN: 1471-4914

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Gong C, Man EPS, Tsoi H, Lee TKW, Lee P, Ma S-T, Wong L-S, Luk M-Y, Rakha EA, Green AR, Ellis IO, Lam EW-F, Cheung K-L, Khoo U-Set al., 2018, BQ323636.1, a Novel Splice Variant to NCOR2, as a Predictor for Tamoxifen-Resistant Breast Cancer, CLINICAL CANCER RESEARCH, Vol: 24, Pages: 3681-3691, ISSN: 1078-0432

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Yao S, Fan LY-N, Lam EW-F, 2018, The FOXO3-FOXM1 axis: A key cancer drug target and a modulator of cancer drug resistance, SEMINARS IN CANCER BIOLOGY, Vol: 50, Pages: 77-89, ISSN: 1044-579X

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Laphanuwat P, Likasitwatanakul P, Sittithumcharee G, Thaphaengphan A, Chomanee N, Suppramote O, Ketaroonrut N, Charngkaew K, Lam EW-F, Okada S, Panich U, Sampattavanich S, Jirawatnotai Set al., 2018, Cyclin D1 depletion interferes with oxidative balance and promotes cancer cell senescence, JOURNAL OF CELL SCIENCE, Vol: 131, ISSN: 0021-9533

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Laphanuwat P, Likasitwatanakul P, Sittithumcharee G, Thaphaengphan A, Chomanee N, Suppramote O, Ketaroonrut N, Charngkaew K, Lam EWF, Okada S, Panich U, Sampattavanich S, Jirawatnotai Set al., 2018, Cyclin D1 depletion interferes with oxidative balance and promotes cancer cell senescence, Journal of Cell Science, Vol: 131, ISSN: 0021-9533

© 2018. Published by The Company of Biologists Ltd. Expression of cyclin D1 (CCND1) is required for cancer cell survival and proliferation. This is presumably due to the role of cyclin D1 in inactivation of the RB tumor suppressor. Here, we investigated the pro-survival function of cyclin D1 in a number of cancer cell lines. We found that cyclin D1 depletion facilitated cellular senescence in several cancer cell lines. Senescence triggered by cyclin D1 depletion was more extensive than that caused by the prolonged CDK4 inhibition. Intriguingly, the senescence caused by cyclin D1 depletion was independent of RB status of the cancer cell. We identified a build-up of intracellular reactive oxygen species in the cancer cells that underwent senescence upon depletion of cyclin D1 but not in those cells where CDK4 was inhibited. The higher ROS levels were responsible for the cell senescence, which was instigated by the p38-JNKFOXO3a- p27 pathway. Therefore, expression of cyclin D1 prevents cancer cells from undergoing senescence, at least partially, by keeping the level of intracellular oxidative stress at a tolerable sublethal level. Depletion of cyclin D1 promotes the RB-independent pro-senescence pathway and the cancer cells then succumb to the endogenous oxidative stress levels.

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Zhang B, Fu D, Xu Q, Cong X, Wu C, Zhong X, Ma Y, Lv Z, Chen F, Han L, Qian M, Chin YE, Lam EW-F, Chiao P, Sun Yet al., 2018, The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1, NATURE COMMUNICATIONS, Vol: 9, ISSN: 2041-1723

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de Moraes GN, Ji Z, Fan LY-N, Yao S, Zona S, Sharrocks AD, Lam EW-Fet al., 2018, SUMOylation modulates FOXK2-mediated paclitaxel sensitivity in breast cancer cells, ONCOGENESIS, Vol: 7, ISSN: 2157-9024

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Peng F, Wang J-H, Fan W-J, Meng Y-T, Li M-M, Li T-T, Cui B, Wang H-F, Zhao Y, An F, Guo T, Liu X-F, Zhang L, Lv L, Lv D-K, Xu L-Z, Xie J-J, Lin W-X, Lam EW-F, Xu J, Liu Qet al., 2018, Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia (vol 37, pg 1062, 2017), ONCOGENE, Vol: 37, Pages: 1119-1119, ISSN: 0950-9232

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Peng F, Wang J-H, Fan W-J, Meng Y-T, Li M-M, Li T-T, Cui B, Wang H-F, Zhao Y, An F, Guo T, Liu X-F, Zhang L, Lv L, Lv D-K, Xu L-Z, Xie J-J, Lin W-X, Lam EW-F, Xu J, Liu Qet al., 2018, Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia, ONCOGENE, Vol: 37, Pages: 1062-1074, ISSN: 0950-9232

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Alasiri G, Fan LY-N, Zona S, Goldsbrough IG, Ke H-L, Auner HW, Lam EW-Fet al., 2018, ER stress and cancer: The FOXO forkhead transcription factor link, MOLECULAR AND CELLULAR ENDOCRINOLOGY, Vol: 462, Pages: 67-81, ISSN: 0303-7207

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Saavedra-Garcia P, Fan LY-N, Lam EW-F, 2018, Multifaceted link between metabolism and cancer, MOLECULAR AND CELLULAR ENDOCRINOLOGY, Vol: 462, Pages: 65-66, ISSN: 0303-7207

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Saavedra-Garcia P, Nichols K, Mahmud Z, Fan LY-N, Lam EW-Fet al., 2018, Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis, MOLECULAR AND CELLULAR ENDOCRINOLOGY, Vol: 462, Pages: 82-92, ISSN: 0303-7207

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Asaduzzaman M, Constantinou S, Min H, Gallon J, Lin M-L, Singh P, Raguz S, Ali S, Shousha S, Coombes RC, Lam EW-F, Hu Y, Yague Eet al., 2018, Tumour suppressor EP300, a modulator of paclitaxel resistance and stemness, is downregulated in metaplastic breast cancer (vol 163, pg 461, 2017), BREAST CANCER RESEARCH AND TREATMENT, Vol: 167, Pages: 605-606, ISSN: 0167-6806

JOURNAL ARTICLE

Monteiro LJ, Cubillos S, Sanchez M, Acuña-Gallardo S, Venegas P, Herrera V, Lam EW-F, Varas-Godoy M, Illanes SEet al., 2018, Reduced FOXM1 Expression Limits Trophoblast Migration and Angiogenesis and Is Associated With Preeclampsia., Reprod Sci

Trophoblast cells are often compared to highly invasive carcinoma cells due to their capacity to proliferate in hypoxic conditions and to exhibit analogous vascular, proliferative, migratory, and invasive capacities. Thus, genes that are important for tumorigenesis, such as forkhead box M1 ( FOXM1) may also be involved in processes of trophoblast invasion. Indeed, we found Foxm1 protein and messenger RNA (mRNA) levels decreased as gestational age increased in rat's placentae. Accordingly, when mimicking early placental events in vitro, protein and mRNA expression of FOXM1 increased from 21% to 8% O2, reaching its highest expression at 3% oxygen tension, which reflects early implantation environment, and dropping to very low levels at 1% O2. Remarkably, FOXM1 silencing in JEG-3 cells was able to significantly decrease migration by 27.9%, in comparison with those cells transfected with control siRNA. Moreover, angiogenesis was compromised when conditioned media (CM) from FOXM1-siRNA -JEG-3 (3% O2) was added to human umbilical vein endothelial cells (HUVEC) cells; however, when CM of JEG-3 cells overexpressing FOXM1 at 1% O2 was added, the ability of HUVEC to form tubule networks was restored. Additionally, quantitative real-time polymerase chain reaction (PCR) assays of FOXM1 knockdown and overexpression experiments in JEG-3 cells revealed that the depletion of FOXM1 at 3% O2 and overexpression of FOXM1 at 1% O2 led to downregulation and upregulation of vascular endothelial growth factor transcriptional (VEGF) levels, respectively. Conversely, we also observed deregulation of FOXM1 in placentae derived from pregnancies complicated by preeclampsia (PE). Therefore, we demonstrate that FOXM1 may be a new regulatory protein of early placentation processes and that under chronic hypoxic conditions (1% O2) and in patients with severe PE, its levels decrease.

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Roig B, Rodriguez-Balada M, Samino S, Lam EW-F, Guaita-Esteruelas S, Gomes AR, Correig X, Borras J, Yanes O, Guma Jet al., 2017, Metabolomics reveals novel blood plasma biomarkers associated to the BRCA1-mutated phenotype of human breast cancer, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322

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Lyu Y, Lou J, Yang Y, Feng J, Hao Y, Huang S, Yin L, Xu J, Huang D, Ma B, Zou D, Wang Y, Zhang Y, Zhang B, Chen P, Yu K, Lam EW-F, Wang X, Liu Q, Yan J, Jin Bet al., 2017, Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and - independent pathways, LEUKEMIA, Vol: 31, Pages: 2543-2551, ISSN: 0887-6924

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Li S-S, Xu L-Z, Zhou W, Yao S, Wang C-L, Xia J-L, Wang H-F, Kamran M, Xue X-Y, Dong L, Wang J, Ding X-D, Bella L, Bugeon L, Xu J, Zheng F-M, Dallman MJ, Lam EW-F, Liu Qet al., 2017, p62/SQSTM1 interacts with vimentin to enhance breast cancer metastasis, CARCINOGENESIS, Vol: 38, Pages: 1092-1103, ISSN: 0143-3334

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Han L, Xu J, Xu Q, Zhang B, Lam EW-F, Sun Yet al., 2017, Extracellular vesicles in the tumor microenvironment: Therapeutic resistance, clinical biomarkers, and targeting strategies, MEDICINAL RESEARCH REVIEWS, Vol: 37, Pages: 1318-1349, ISSN: 0198-6325

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Yang N, Wang C, Wang Z, Zona S, Lin S-X, Wang X, Yan M, Zheng F-M, Li S-S, Xu B, Bella L, Yong J-S, Lam EW-F, Liu Qet al., 2017, FOXM1 recruits nuclear Aurora kinase A to participate in a positive feedback loop essential for the self-renewal of breast cancer stem cells, ONCOGENE, Vol: 36, Pages: 3428-3440, ISSN: 0950-9232

JOURNAL ARTICLE

Asaduzzaman M, Constantinou S, Min H, Gallon J, Lin M-L, Singh P, Raguz S, Ali S, Shousha S, Coombes RC, Lam EW-F, Hu Y, Yague Eet al., 2017, Tumour suppressor EP300, a modulator of paclitaxel resistance and stemness, is downregulated in metaplastic breast cancer, BREAST CANCER RESEARCH AND TREATMENT, Vol: 163, Pages: 461-474, ISSN: 0167-6806

JOURNAL ARTICLE

Lau C-HE, Tredwell GD, Ellis JK, Lam EW-F, Keun HCet al., 2017, Metabolomic characterisation of the effects of oncogenic PIK3CA transformation in a breast epithelial cell line, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322

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Fan LY-N, Saavedra-García P, Lam EW-F, 2017, Dataset of the human homologues and orthologues of lipid-metabolic genes identified as DAF-16 targets their roles in lipid and energy metabolism., Data Brief, Vol: 11, Pages: 606-610, ISSN: 2352-3409

The data presented in this article are related to the review article entitled 'Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis' (Saavedra-Garcia et al., 2017) [24]. Here, we have matched the DAF-16/FOXO3 downstream genes with their respective human orthologues and reviewed the roles of these targeted genes in FA metabolism. The list of genes listed in this article are precisely selected from literature reviews based on their functions in mammalian FA metabolism. The nematode Caenorhabditis elegans gene orthologues of the genes are obtained from WormBase, the online biological database of C. elegans. This dataset has not been uploaded to a public repository yet.

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This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

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