Studying the genetic and metabolic regulation of childhood development and cancers.
Childhood cancers are diseases of dysregulated development. Our research seeks to understand the genetic and metabolic mechanisms that control mammalian development and how its dysregulation causes devastating childhood diseases, including cancer.
Metabolic programming during development
The developmental processes after birth are primarily linked to metabolic dynamics, in part through the regulation of tissue-specific gene expression in response to nutrient availability and hormonal signaling. During the course of postnatal development, significant metabolic changes take place to enable rapid growth and functional maturation of the developing organs. We work to dissect the metabolic programs that orchestrate the development of liver, kidney and brain ̶ the organs often prominently affected by severe metabolic decompensation in infancy, childhood and adolescence. Using a multidisciplinary approach including metabolomics, transcriptomics, epigenomics and single-cell genomics, we have identified new metabolic switches that involve the dynamic regulation of mitochondrial programming as critical players in this process.
Regulation of metabolism in pediatric cancers
Altered cellular metabolism is a hallmark of human cancer that creates a unique dependency to support malignant tumor growth. Pediatric tumors often differ significantly from adult counterparts in their etiology, mutational burden and spectrum, cell-of-origin, and/or epigenetic landscapes. In contrast to significant advances in metabolic studies of adult cancers, there remains a dearth of knowledge regarding the nature, characteristics, and regulation of metabolic programs in pediatric tumors. Our research focuses on childhood cancer metabolism by addressing several key questions, including how tumor-initiating cells progressively rewire metabolic programs during early development, what malignant properties are enabled by oncogenic lesions in developing cells and organs, and how we can modulate these metabolic alterations as selective vulnerabilities for therapeutic benefit in children.
Functional metabolomics and lipidomics
With the advances in mass spectrometry technologies, we have developed a robust analytical platform by integrating large-scale metabolic profiling and targeted functional assays, including metabolomics, lipidomics and metabolic flux analysis. This approach enables a systematic investigation of metabolic phenotypes, programming and reprogramming across a wide spectrum of development and disease models and patient-derived samples.
Through this research framework, we have identified the functional impact of genetic variants in inherited metabolic diseases, the metabolic mechanism underlying dysregulated purine biosynthesis in human cancers, and the rewired metabolic processes in the pathophysiology of common red blood cell disorders. Our ongoing efforts are focused on the development of high-sensitivity and high-capacity metabolomic techniques, understanding the metabolic interactions within the tumor microenvironment, and deciphering the intricacies of cell-host metabolic crosstalk in developmental processes and cancer pathogenesis.