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.
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?
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.
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.