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Research Interests

Our group is interested in understanding the metabolic organization and its regulation of cellular processes like growth, proliferation and differentiation.While the role of thermodynamic and kinetic principles in organizing and driving metabolic reactions are understood, the specific interplay of metabolites and enzymes in modulating signaling and gene transcription is now coming to the fore. During embryonic development and in metabolic diseases such as cancer, cellular fates like cell proliferation and differentiation are associated with specific metabolic states. Using a combination of functional genomics with advanced mass spectrometry, imaging and computational modelling, we aim to understand the metabolic cross-talk with signaling and gene transcription networks in development and disease. The specific questions that we ask are:

1. How does sub-cellular metabolic compartmentalization help in cancer progression?

In solid tumors, cancer cells face nutrient limitation due to poor vasculature. Under these conditions, cancer cells rewire their metabolism and evolve to acquire alternate nutrients for their growth and proliferation. We and others have previously shown that acetate is one such nutrient that is scavenged by hypoxic and lipid deprived cancer cells (Schug et al., (2015) Cancer Cell. 27(1):57-71., Comerford et al., (2014) Cell159(7):1591-602; Bulusu et al., (2017) Cell Rep.18(3):647-658). Acetate was thought to feed into a common nucleo-cytosolic acetyl-CoA pool to fuel lipid synthesis and histone acetylation. However, our study showed that under hypoxic conditions, nuclear and cytosolic acetyl-CoA pools are compartmentalized by a kinetic barrier enabling exogenous acetate to channel directly into lipid synthesis (Figure 1). We are now pursuing further studies to understand such flux barriers in metabolic compartmentalization and how these help in cancer progression.

Figure 1: Acetyl-CoA compartmentalization in hypoxic and lipid deprived cancer cells. Adapted from Bulusu et al. Cell Rep.18(3):647-658 (2017)

2. How do dynamic changes in metabolites effect gene expression networks?

Metabolites such as acetyl-CoA and S-adenosyl methionine are important cofactors for DNA and chromatin modifying enzymes. How fluctuations in these metabolites lead to changes in gene expression is being investigated. We are currently developing novel genetically encoded fluorescence-based sensors for such metabolites using protein engineering and modelling approaches with the aim to understand their sub-cellular dynamics.

3. Role of metabolic gradients incancer and embryonic development?

Altered metabolic activities of the cancer cells and aberrant vascular development leads to development of metabolic and nutrient gradients in solid tumors. In addition to cancer, we and others have previously shown the existence of a glycolytic gradient in mouse embryonic presomitic mesoderm that is essential for anterior-posterior axis elongation and patterning (Bulusu et al., (2017)Dev Cell.40:331-341; Oginuma et al., (2017) Dev Cell. 40: 342-353) (Figure 2). Such gradients have been proposed to confer robustness to nutrient fluctuations. We are currently dissecting the mechanisms of gradient formation and their role using cell culture models in vitroand in future using mouse models in vivo.

Figure 2: Glycolytic gradient in mouse embryonic presomitic mesoderm. Adapted from Bulusu et al. (2017) Dev Cell. 40: 331-341.