Subhamoy Dasgupta

Research Overview:

Metabolic reprogramming is an essential hallmark of tumor progression and metastasis. Cancer cells use altered metabolic pathways to sustain rapid growth and to overcome enormous stress encountered in tumor microenvironment. Tumor cells constantly alter their metabolic state in response to oncogenic stimuli, nutrient availability, and interaction with immune cells however the precise regulation that precedes the metabolic alteration is poorly understood. We believe information about a tumor cell's metabolic state is integrated into the regulation of transcription, and understanding these regulatory checkpoints will certainly allow us to intervene tumor progression and metastasis. Our lab uses state-of-art facilities such as metabolomics, proteomics, and genomics along with molecular biology techniques to investigate the crosstalk between metabolic signaling and transcriptional networks. Multiple animal model systems including genetically engineered mouse models (GEMMs), patient-derived xenograft (PDX), and syngeneic tumor models are used to investigate metabolic adaptations that promote tumor progression and metastasis.

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, we are understanding the metabolic checkpoints that drive aggressive metastatic cancer that could be exploited as a potential therapeutic target.

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, which is an active area of investigation in our lab.

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 exert 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.

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