RESEARCH
DISCOVERING METABOLIC DYSREGULATION IN CANCER
Metabolic adaptation is one of the essential hallmarks of cancer to sustain replication and survival stress. Based on available nutrients, tumor cells alter their metabolic pathways for the biosynthesis of macromolecules and mitochondrial ATP synthesis. Metabolic reprogramming plays a pivotal role in tumor cell survival during metastatic dissemination, circulation, and colonization in distant organs, thus driving the successful formation of metastatic lesions. Hence, understanding the metabolic checkpoints that drive aggressive metastatic cancer holds promise as an effective therapeutic strategy.
Dysregulation of lipid metabolism is a hallmark of many tumors. The increased demand for de novo lipogenesis is supported by elevated levels of rate-limiting enzymes such as fatty acid synthase (FASN) and stearoyl-CoA desaturase, which are transcriptionally regulated in the nucleus. Mitochondrial citrate is the precursor metabolite required for lipogenesis, which is exported to the cytosol for conversion into acetyl-CoA and subsequently into malonyl CoA for de novo biosynthesis of fatty acids. But how the nuclear transcriptional regulators communicate with mitochondria to signal sustained synthesis of citrate remains unknown. We found mitochondrial aconitase (ACO2) plays a vital role in mitochondrial-nuclear communication, and currently we are investigating underlying mechanisms and enzymatic regulation that promotes lipogenesis in aggressive tumors.
DEFINING TRANSCRIPTIONAL AND EPIGENETIC REGULATION
Cellular adaptation to fuel availability is critical for major cellular decisions, and it requires alterations in metabolic pathways coupled with differential expression of genes to rewire biochemical processes. Mitochondria lay at the core of cellular metabolism, whereas nucleus integrates cellular and environmental signals to activate gene transcription. Intriguingly, many metabolic enzymes can directly sense the nutrient supply and stimulate gene transcription to establish an adaptive response. However how the mitochondrial enzymes modulate gene transcription in response to bioenergetic stress is poorly understood.
One of the most critical steps before transcription could be initiated is the process of chromatin relaxation which is achieved by acetylation of histone proteins. Acetylation of the lysine (K) residues in the N-terminal tail of histone reduces its affinity to the DNA thereby loosening the chromatin and providing greater accessibility to the transcription factors and coregulators for assembly on gene promoters. Thus, acetylation marks on histones dictate gene regulation in an epigenetic manner. Central to this epigenetic regulation remains the ‘availability of acetyl-CoA’ in the nucleus, which is used by the histone acetyl transferases (HATs) for acetylating histone lysine residues. This raises an intriguing scientific question, how acetyl-CoA pool is regulated and maintained in the nucleus to sustain gene activation?
DECODING TUMOR MICROENVIRONMENT AND IMMUNE RESPONSE
Tumor intrinsic metabolic pathways significantly alter the tumor microenvironment (TME). Metabolic stress in TME influences aggressive tumor phenotype and the hypoxic regions within the tumor exerts an increased risk of metastasis by activating transcriptional programs. TME consists of cellular components including stromal cells and immune cells, and characterized by lactic acidosis, hypoxia and secreted tumor-derived factors. We are interested to define whether adaptive changes induced by TME contribute to enhanced invasiveness by allowing cancer cells to acquire cell-autonomous properties favoring site specific metastatic colonization. In addition, altered tumor metabolism promotes an immunosuppressive TME which may diminish efficacy and response rate of immunotherapy. We are investigating the mechanisms that regulate TME properties compromising anti-tumor immune response.