Wai Leong TAM

Cancer progression is orchestrated by complex alterations in cellular behaviors that enable the survival of, and colonization by, cancer cells in the human body. Disturbances in cell states underlie disease progression and clinical outcomes. Underpinning the control of cancer cell states are metabolic reprogramming events, i.e., why are the nutritional needs of cancer cells unique or different? Many fundamental cancer pathways are now known to impinge on cell metabolism, and strategies focusing on disrupting specific metabolic processes to control disease progression have gained considerable interests. Leveraging on functional genomic approaches, and in close collaboration with clinician partners, Dr Wai Leong Tam’s group seeks 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.



Principal Investigator, Cancer Science Institute of Singapore, National University of Singapore
Associate Director, Genome Institute of Singapore, A*STAR
Group Leader, Genome Institute of Singapore, A*STAR
Associate Professor (Adjunct), Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore
Assistant Professor (Adjunct), School of Biological Sciences, Nanyang Technological University

2015 – 2020 Singapore NRF Fellow, National Research Foundation, Singapore
2003 – 2007 A*STAR Graduate Scholarship, A*STAR
2003 – 2006 President’s Graduate Fellowship, NUS
2003 Vice-Chancellor’s List, NUS
2003 Joanna Wong Gold Medal Award, University Scholars Programme, NUS
2002 – 2003 Frazer & Neave Book Prize, Faculty of Science, NUS
2001 – 2003 Raffles Prize, Faculty of Science, NUS
2000 – 2003 Dean’s List (every year), NUS


While significant headways have been made in the development and deployment of therapeutics for some cancers, long-term disease-free responses for most cancers are rare. Drug development efforts have traditionally focused on well-studied kinases, hormones and receptors, resulting in a saturation of targets that already have multiple inhibitors. Adding to this challenge, tumor cells evolve over time, acquire bypass pathways, and gain resistance to multi-generations of drug classes, highlighting the limitations of such approaches. Thus, there is an unmet need to develop newer classes of therapeutic modalities that may be more durable, and well as more innovative ways to control cancer growth and dissemination through the precise control of cell states.



Cellular Energetics: Dysregulated cellular energetics (i.e. cancer metabolism) is a more recent addition to the hallmarks of cancer. The revelation that tumor cells and their associated stromal cells have altered metabolic requirements suggests a way forward in targeting their metabolic states. Several of the most effective drugs that have been in use for many decades target cancer cell metabolism. In fact, the very first chemotherapeutic agent is an anti-metabolite (anti-folate), and it is still used as the standard-of-care more than fifty years since its discovery. This highlights the longevity of anti-metabolites and their immense potential as durable anti-cancer agents. Altered metabolism, such as the avid uptake and utilization of glucose and certain amino acids including serine, glycine and glutamine are well-described. These modes of metabolism appears critical for tumor proliferation in general. Owing to the diverse intratumoral subpopulations that include cancer stem cells and drug resistant cells, further investigations are needed to develop more specific anti-cancer metabolic strategies for durable clinical responses.

What are the metabolites produced and utilized by heterogeneous tumor cells that include CSCs, resistant cells, and disseminated metastatic cells? Why are they uniquely important? How do we exploit the metabolic liabilities of cancer as therapeutic targets?

Cell State Transitions: Cellular heterogeneity at the genomic and transcriptomic levels is a hallmark of tumors. The heterogeneous nature of tumors may be driven by evolution of distinct clonal cell population as a result of selection or through inherent phenotypic plasticity. Cellular plasticity may be enabled by cell state transitions that is regulated through gene expression programs with far-reaching consequences. Cell state transitions include the epithelial vs mesenchymal, stemness vs dedifferentiation, therapy sensitive vs resistance, and local tumor vs metastases. Understanding cellular pathways and programs governing phenotypic plasticity will result in more precise control of cell states and cell fates, thereby providing new opportunities to alter the course of disease progression.

How do we engineer vulnerabilities into specific populations of aggressive cancer cells that will cause them to gain susceptibility to therapy? Can we rewire stemness and differentiation programs in cancer cells?

Lab Members

Selected Publications

1. 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, in press. #Corresponding authors

2. 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, Kas?m 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

3. 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

4. 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.

5. 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

6. Pattabiraman, D.R., Bierie, B., Kober, K., Krall, J., Zill, C., Reinhardt, F., Tam, W.L. and Weinberg, R.A. (2016). Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability. Science. 351:6277

7. Ye, X., Tam, W.L., Shibue, T., Kaygusuz, Y., Reinhardt, F., Eaton, E. Weinberg, R.A. (2015). Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature. 525:256-60.

8. Tam, W.L. and Weinberg, R.A. (2013). The epigenetics of epithelial-mesenchymal plasticity in cancer. Nature Medicine. 19:1438-1449

9. Tam, W.L., Lu, H., Buikhuisen, J., Soh, B.S., Lim, E., Reinhardt, F., Wu, Z.J., Krall, J.A., Bierie, B., Guo, W., Chen, X., Liu, X.S., Brown, M., Lim, B. and Weinberg, R.A. (2013). Protein kinase C ? is a central signaling node and therapeutic target for breast cancer stem cells. Cancer Cell. 24:347-364

10. Han, J., Yuan, P., Yang, H., Zhang, J., Soh, B.S., Li, P., Lim, S.L., Cao, S.Y., Tay, J.L.,  Orlov, Y.L., Lufkin, T., Ng, H.H., Tam, W.L.# and Lim, B.# (2010). Tbx3 improves the germ-line competency of induced pluripotent stem cells. Nature. 463:1096-1100. #Corresponding authors