TAM Wai Leong

RESEARCH

Visit our Lab Website @ https://www.tamlab.org/

LinkedIn: https://sg.linkedin.com/in/wai-leong-tam-7632375

***Career Opportunities***
***We are recruiting BIOINFORMATICIAN, POSTDOCS, and GRADUATE STUDENTS!***

The Tam Laboratory harnesses functional genomics to understand dysregulation in cellular metabolism and cell state perturbations for revealing principles of cancer stemness, resistance and metastasis.

Cancer progression is orchestrated by complex alterations in gene functions and cellular behaviors. Perturbations in cell states, such as stemness vs differentiation programs, epithelial vs mesenchymal transitions, treatment resistance vs naïve responses, and localized vs metastatic phenotypes, underlie disease progression and clinical outcomes. Leveraging on genome-scale functional genomic approaches, and in close collaboration with clinician partners, we seek to gain insights into the precise control of cancer cell states, and specific targeting of metabolic pathways, for the development of selective therapeutics against cancer resistance and metastasis. We apply advanced integrative methodologies that include genomics, transcriptomics, computational analyses, metabolomics, high-throughput chemical-genetic screens, whole-genome engineering, biophysics and organoids, for enabling discoveries with clear translational or intervention value. 

Research Themes

1. Cell state plasticity: Transitions between cell states (stemness vs differentiated, epithelial vs mesenchymal) contribute towards the adaptations of cancer cells during malignant progression. Our ongoing research focuses on how cancer stemness drive resistance, and how the epithelial-mesenchymal transition promotes metastasis (Challenge 1). How do we engineer vulnerabilities into cancer cells that will cause them to gain susceptibility to therapy through exploiting the principles of synthetic lethality? Can we rewire stemness and differentiation programs in cancer cells? How does tumor microenvironmental cells influence cellular plasticity?
   
   
2. Metabolic regulation: Cancer is a metabolic disease. Metabolic alteration is a hallmark of malignancy recognized almost a century ago. The preponderance of cancer cells to utilize glucose was first observed by Otto Warburg in the 1920s, but it is now clear that the Warburg effect represents only the tip of the iceberg pertaining to the wide range of metabolic derangements accompanying malignant transformation and progression. Our research program seeks to investigate unique metabolic adaptations that are crucial for determining a spectrum of pliable cell states, and extending into metabolic crosstalk of the tumor microenvironment. In view of tumor heterogeneity, principles of how distinct metabolic alterations arise from variations in phenotypic cell states need to be more precisely defined (Challenge 2). Transitions between cell states contribute towards the adaptations of cancer cells during malignant progression. Our recent findings below have exemplified how the disruption of metabolic processes may be exploited to target specific cell states or prevent the acquisition of aggressive phenotypes.
   
   
3. Niche biology: Cancer cells utilize nutrients in a cell-autonomous manner, but cell-extrinsic factors arising from the tumor microenvironment have been recently observed. The notion that stromal and tumor cells engage in metabolic exchange is nascent. For instance, lactate produced as a by-product of fibroblast cells can be used as an energy source by lung carcinoma cells to fuel their biosynthetic needs. From an opposite perspective, however, the manner by which nutrients secreted by the microenvironmental cells may program metabolic addiction in tumor cells to induce therapeutic vulnerability has not been explored (Challenge 3). Understanding the extent and nature of such metabolic exchanges between tumor and microenvironment cells is timely; it can inform on the use therapeutics to target metabolic vulnerabilities, including their impact on immune-oncometabolism.

Selected Publications

• Tran TTT_, Phung CD, Yeo BZJ, Prajogo RC, Jayasinghe MK, Yuan J, Trinh NM, Yeo EYM, Dahai L, Goh BC, Tam WL^#, Le MTN^#. (2024) Customized design of ASOs targeting EGFR driver mutants for personalized treatment of Non-Small Cell Lung Cancer. EBioMedicine. Sep 19;108:105356. doi:10.1016/j.ebiom.2024.105356.. ^#Corresponding authors
• Chen JB^#,*, Kaya NA*, Zhang Y*, Kendarsari I, Ling WH, Phua CZJ, Lai H, Yang H, Lu B, Lim JQ, Ma S, Chew SC, Chua KP, Alvarez JJS, Wu L, , Ooi L, Chung AY-F,  Cheow PC, Kam JH, Kow AW-C, Ganpathi IS, Chanwat R, Thammasiri J, Yoong BK, Ong DB-L, Lim J, de Villa VH, Dela Cruz RD, Loh TJ, Wan WK, Leow WQ, Yang Y, Liu J, Skanderup AJ, Pang YH, Ting GS, Madhavan K, Lim TK-H, Bonney G, Goh BKP, Chew V, Dan YY, Toh HC, Foo RS-Y, Tam WL^#, Zhai W^#, Chow PK-H^#. (2024) A multimodal atlas of hepatocellular carcinoma reveals convergent evolutionary paths and the ‘bad apple’ effect on clinical trajectory. Journal of Hepatology. doi.org/10.1016/j.jhep.2024.05.017. ^#Corresponding authors
• Alcolea MP, Alonso-Curbelo D, Ambrogio C, Bullman S, Correia AL, Ernst A, Halbrook CJ, Kelly GL, Lund AW, Quail DF, Ruscetti M, Shema E, Stromnes IM, Tam WL. (2024) Cancer Hallmarks: Piecing the Puzzle Together. Cancer Discovery. 2024 Apr 4;14(4):674-682. doi: 10.1158/2159-8290.CD-24-0097.
• Lee YF, Phua CZJ, Yuan J, Zhang B, Lee MY, Koh CWQ, Lim EKH, Chen J, Lim Y, Lee JHJ, Skanderup AJ, Wang Z, Zhai W, Tan NS, Tay Y, Tan DSW, Tam WL. (2024) PARP4 regulates intronic splicing through hnRNPM in lung adenocarcinoma. Genome Medicine. Jul 22;16(1):91. doi: 10.1186/s13073-024-01328-1.
• Lee YF, Chen L, Chew V, Chow EK, Deng LW, Hunziker W, Lee ASG, Leong G, Ngeow J, Pervaiz S, Sabapathy K, Skanderup AJ, Sundar R, Tay Y, Virshup DM, Wong SH, Tergaonkar V, Tam WL. (2024) Pushing the Frontiers of Cancer Research: Highlights from the Frontiers in Cancer Science Conference 2023. Cancer Research. Apr 15;84(8):1195-1198. doi: 10.1158/0008-5472.CAN-24-0721.
• Lee MY, Tam WL. (2023) Multimodal metabolomics pinpoint new metabolic vulnerability in colorectal cancer. Nature Metabolism. Aug; 5(8):1255-1257. doi: 10.1038/s42255-023-00852-5
• Wu Z, Tam WL. (2021) A new foe in folate metabolism. Nature Metabolism. 18 Nov 2021. 10.1038/s42255-021-00474-9
• Loo SY, Toh LP, Xie WH, Pathak E, Tan W, Ma S, Lee MY, Shatishwaran S, JZZ Yeo, Yuan J, Ho YY, EKL Peh, Muniandy M, Torta F, Chan J, Tan T, Sim YR, Tan V, Tan B, Madhukumar M, Yong WS, Ong KW, Wong CY, Tan PH, Yap YS, Deng LW, Dent R, Foo R, Wenk MR, Lee SC, Ho YS, Lim EH^#, Tam WL^#. (2021) Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer. Science Advances. Oct 8. 7(41):eabh2443. doi: 10.1126/sciadv.abh2443. ^#Corresponding authors
• Li Z, Wang Z, Lee MC, Zenkel M, Peh E, Ozaki M, Chan A, Chen S, Nakano S, Williams SEI, Orr A, Nakano M, Kobakhidze N, Zarnowski T, Popa-Cherecheanu A, Mizoguchi T, Manabe S, Hayashi K, Kazama S, Inoue K, Mori Y, Miyata K, Sugiyama K, Higashide T, Chihara E, Ideta R, Ishiko S, Yoshida A, Yanagi M, Kiuchi Y, Ohashi T, Sakurai T, Sugimoto T, Chuman H, Aihara M, Inatani M, Mori K, Ikeda Y, Ueno M, Gaston D, Bedard K, Greer WL, Chichua G, Tabagari S, Founti P, Sim KS, Chatzikyriakidou A, Pappas T, Anastasopoulos E, Lambropoulos A, Kosior-Jarecka E, Cheong A, Li A, Lukasik U, Nongpiur ME, Husain R, Wong TY, Perera SA, Álvarez L, García M, González-Iglesias H, Rodríguez-Calvo PP, Fernández-Vega L, Martinon-Torres F, Salas A, Oguz Ç, Tamcelik N, Atalay E, Batu B, Irkec M, Aktas D, Kasım B, Astakhov YS, Astakhov SY, Akopov EL, Emelyanov A, Vysochinskaya V, Uebe S, Krumbiegel M, Welge-Luessen U-C, Mardin C, Berner D, Hoja U, Kruse FE, , Reis A, Moebus S, Carmichael TR, Hauser M, Ramsay M, Mossböck G, Nilgun Y, Tashiro K, Konstas AGP, Coca-Prados M, Foo JN, Sotozono C, Kubota T, Dubina M, Topouzis F, Ritch R, Pasutto F, Wiggs J, Schloetzer-Schrehardt U^#, Ho YS^#, Aung T^#, Tam WL^#, Khor CC^#. Association of rare CYP39A1 variants with exfoliation syndrome involving the anterior chamber of the eye. (2021) Journal of the American Medical Association. 22 Feb. ^#Corresponding authors
• Sun J, Prabhu N, Tang J, Yang F, Jia L, Guo J, Xiao K, Tam WL^#, Nordlund P^#, Dai L^#. (2021) Recent advances in proteome-wide label-free target deconvolution for bioactive small molecules. Medicinal Research Reviews. 2021 Feb 3. doi: 10.1002/med.21788. ^#Corresponding authors
• Tan, J.L., Li, F., Yeo, J.Z., Yong, K.J., Bassal, M.A., Ng, G.H., Lee, M.Y., Leong, C.Y., Tan, H.K., Wu, C.S., Liu, B.H., Chan, T.H., Tan, Z.H., Chan, Y.S., Wang, S., Lim, Z.H., Toh, T.B., Hooi, L., Low, K.N., Ma, S., Kong, N.R., Stein, A.J., Wu, Y., Thangavelu, M.T,, Suzuki, A., Periyasamy, G., Asara, J.M., Dan, Y.Y., Bonney, G.K., Chow, E.K., Lu, G.D., Ng, H.H., Kanagasundaram, Y., Ng, S.B., Tam, W.L.^#, Tenen, D.G.^#, and Chai, L.^# (2019) New High-throughput Screen Identifies Compounds That Reduce Viability Specifically In Liver Cancer Cells That Express High Levels of SALL4 by Inhibiting Oxidative Phosphorylation. Gastroenterology. Aug 22. pii: S0016-5085(19)41242-0. doi: 10.1053/j.gastro.2019.08.022. ^#Corresponding authors
• Wang, Z., Yip, L.Y., Lee, J.H.J., Wu, Z., Chew, H.Y., Chong, P.K.W., Teo, C.C., Ang, H.Y.K, Peh, K.L.E., Yuan, J., Choo, L.S.K., Basri, N., Jiang, X., Yu, Q.,  Hillmer, A., Lim, T.K.H, Takano, A., Tan, E.H., Tan, D.S.W., Ho, Y.S., Lim, B.^#, and Tam, W.L.^# (2019) Methionine is a metabolic dependency of tumor-initiating cells. Nature Medicine. 25(5):825-837. ^#Corresponding authors
• Tan, W.L., Jain, A., Takano, A., Newell, E.W., Iyer, N.G., Lim, W.T., Tan, E.H., Zhai, W., Hillmer, A.M., Tam, W.L., and Tan, D.S.W. (2016) Novel therapeutic targets on the horizon for lung cancer. Lancet Oncology. 17:e347
• Zhang, W.C., Chin, T.M., Yang, H., Nga, M.N., Lunny, D.P., Lim, E.K.H., Sun, L.L., Pang, Y.H., Leow, Y.N., Malusay, S.R.Y., Lim, P.X.H., Lee, J.Z., Tan, B.J.W., Shyh-Chang, N, Lim, E.H., Lim, W.T., Tan, D.S.W., Tan, E.H., Tai, B.C., Soo, R.A., Tam, W.L.^# and Lim, B.^# (2016) Tumor-initiating cell-specific miR-1246 and miR-1290 expression converge to promote non-small cell lung cancer progression. Nature Communications. 7:11702.  ^#Corresponding authors