Han Lab

Nutrient Signaling, Amino Acid Metabolism, and Metabolic Precision Oncology

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1. Beyond Kinases: Expanding the Druggable Landscape in Cancer

 

Since the success of Gleevec, cancer drug development has largely focused on signaling mediators such as kinases. While this strategy has yielded several FDA-approved drugs, the number of effective targets remains limited and heavily biased toward canonical signaling pathways. Moreover, many kinase-targeted therapies suffer from modest efficacy and rapid emergence of resistance due to tumor heterogeneity.

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To overcome these limitations, our laboratory seeks to identify therapeutic targets that are:

• Mechanistically fundamental

• Metabolically essential

• Tolerant to tumor heterogeneity

• Less prone to resistance development

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We focus on amino acid metabolism and amino acid signaling as underexplored but highly promising therapeutic vulnerabilities in cancer.

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2. Amino Acids as Signaling Molecules

 

Amino acids are not merely substrates for protein synthesis. They function as signaling nutrients that regulate:

• mTORC1 activation

• Autophagy

• Translation

• Cell growth and death

• Circadian rhythm

• Metabolic rewiring

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We investigate how intracellular amino acid availability is sensed and transduced into signaling outputs that control cellular physiology.

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Our central question is:

How is amino acid signaling established at the molecular level, and how does its dysregulation drive human disease?

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3. Aminoacyl-tRNA Synthetases (ARSs) as Intracellular Amino Acid Sensors

 

Translation is dynamically regulated by intracellular amino acid and ATP availability. Amino acid levels are determined by a balance of:

• Extracellular uptake

• Metabolic synthesis

• Protein turnover

• Aminoacyl-tRNA formation

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Aminoacyl-tRNA synthetases (ARSs) catalyze the first step of protein synthesis by ligating amino acids to their cognate tRNAs. Because ARSs simultaneously recognize amino acids, tRNAs, and ATP, they are uniquely positioned to function as intracellular nutrient sensors.

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A landmark example is leucyl-tRNA synthetase (LRS), which acts as an intracellular leucine sensor regulating the mTORC1 pathway. LRS interacts with Rag GTPases in a leucine-dependent manner and functions as a GAP for RagD, thereby activating mTORC1.

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Our research aims to:

• Define ARSs as amino acid sensors beyond translation

• Identify novel sensing mechanisms

• Elucidate noncanonical regulatory functions of ARSs

• Link amino acid sensing to cancer and degenerative diseases

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4. Metabolic Rewiring in Cancer: Amino Acids at the Core

 

Cancer cells exhibit profound metabolic reprogramming. While much attention has focused on glycolysis (Warburg effect), tumor metabolism extends far beyond glucose utilization.

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In cancer cells:

• Aerobic glycolysis supports biosynthetic precursor production

• Glutaminolysis fuels TCA cycle intermediates

• Amino acid–derived metabolites regulate epigenetics and redox balance

• Metabolic intermediates support nucleotide, lipid, and protein synthesis

 

We investigate how amino acid metabolism differs between normal and cancer cells and how these differences create therapeutic windows.

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Our work extends beyond energy metabolism to explore:

• Mitochondrial amino acid transport systems

• Metabolite-driven signaling

• Amino acid–dependent epigenetic regulation

• Metabolic control of tumor–immune interactions

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5. Mitochondrial Amino Acid Transport and Novel Therapeutic Targets

 

Emerging evidence indicates that mitochondrial amino acid flux is a critical determinant of cancer cell survival. Our laboratory has identified and characterized mitochondrial glutamine transport systems that regulate:

• αKG production

• Lactate balance

• TCA cycle activity

• Redox homeostasis

• Tumor growth

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We integrate structural biology, computational modeling, and experimental validation to develop selective inhibitors targeting mitochondrial nutrient transport.