How does a single mutant cell trigger disease pathogenesis?
Tissue Genetics
Functional Interrogation of Somatic Mosaicism
The acquisition of deleterious somatic mutations within single cells is the first step in many age-related diseases, including cancer. Initially, a lone mutant cell may have a negligible effect, and pathogenesis begins as the mutant cell clonally expands and becomes more prevalent in a tissue. Despite the critical importance of somatic mutagenesis for understanding disease progression, we still have a limited knowledge of its underlying molecular and cellular principles. One of the vital forces at play during clonal expansion of mutant cells is fitness-based selection. Like natural selection during organismal evolution, selective forces within tissues are likely to play critical roles in shaping mutant cell trajectories, thus controlling the timing of disease onset. To investigate how mutant cells propagate within living tissues and ultimately disrupt their function, my research group will use the fruit fly Drosophila melanogaster and leverage molecular and cell biology, genetic, imaging, and multi-omics approaches to:
1. Define stages of pathogenesis from the emergence of an engineered somatic mutation to tissue phenotypes
2. Determine the molecular properties and cellular phenotypes of clones carrying human disease-linked mutations
3. Investigate how the selective and competitive forces that emerge from the interaction between mutant and wild-type
cells affect the mutant cells’ behavior
4. Interrogate how varied genetic backgrounds and environmental factors influence the clonal expansion and deleterious
effects of mutant cells in vivo
Tumor Cell Plasticity in Cancer Evolution
Cellular and phenotypic plasticity play a critical role in cancer initiation and progression. The first step of cancer development is the hyper-proliferation of tumor cells. Mutations in Ras, which encodes a small GTPase, are detected in a wide range of cancers. Intriguingly, cancer whole-genome sequencing reveals tissue-selectivity of Ras oncogenic mutations. Our recent results reveal unexpected impacts of oncogenic allele-dependent cellular behaviors on the expansion of tumor cells.
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Genetic Heterogeneity in Cell-Cell Communication
Somatic mutations initially affect a single cell, potentially generating a clone of heterozygous mutant cells within tissues. Most somatic mutations are assumed to be silent because the majority of mutations studied in animal models are recessive based on Mendel’s Law of Dominance. Accordingly, the “two-hit” model remains the central paradigm of cancer genetics. Our recent findings suggest a “one-hit” mechanism for some instances of disease pathogenesis associated with spontaneous somatic mutations
Structure-Based Drug Discovery
The proto-oncogene Ras is often mutated in various cancers. Despite this, Ras proteins have traditionally been considered "undruggable." Our team harnesses the synergy of fly genetics and machine-learning strategies to develop drugs targeting oncogenic Ras proteins.
