Research
Research
What makes a cancer cell metastasize?
Metastasis causes most cancer deaths, yet its molecular and cellular mechanisms remain poorly understood. Our lab integrates genetic, molecular, cellular, organismal, and clinical approaches to discover the regulators of metastatic disease and to translate that biology into therapies. We have advanced two of our discoveries into human clinical trials, identified the first hereditary genetic determinants of metastasis, uncovered tRNA-mediated mechanisms of gene regulation, and revealed an unexpected role for the nervous system in cancer progression.
Metastasis Biology & Genetics
We have identified critical genes that regulate metastasis formation in common cancers and provided the first evidence that hereditary genetics shapes whether a primary tumor becomes metastatic. Our current work uses molecular, genetic, biochemical, pharmacological, imaging, and clinical-association approaches to discover additional heritable factors that drive metastatic progression and to understand their mechanisms of action within the metastatic niche.
Metastasis Therapy
Our discovery of critical metastasis-regulating genes has revealed new therapeutic paths. We are developing small-molecule and antibody-based therapeutics designed to prevent and eradicate metastatic disease. Two of these programs, advanced through our biotechnology partner Inspirna, have demonstrated proof-of-concept in advanced-stage and refractory cancers in human clinical trials. We are now building anti-metastatic combination regimens with the goal of achieving curative outcomes.
tRNA-Mediated Gene Regulation in Cancer
We discovered that specific transfer RNAs are dynamically modulated as cancer cells become metastatic — a surprising finding given the traditional view of tRNAs as static adaptor molecules. These tRNA modulations enable selective enhanced translation of pro-metastatic genes. We have found that such tRNA modulations can occur beyond cancer and can be regulated by dietary amino acids. We are using molecular, genetic, and biochemical approaches to dissect this non-canonical gene regulatory mechanism and to understand how dietary inputs influence tRNA dynamics across multiple diseases.
Regulation of Cancer Metastasis by the Nervous System
We have found that during breast cancer progression, primary tumors become increasingly innervated by sensory neurons. Cancer cells enhance the activity of these neurons, leading to the release of sensory neuropeptides that act back on the cancer cells to promote invasiveness and metastatic growth. Our current work investigates how cancer cells activate sensory neurons, how neuropeptides elicit pro-metastatic gene-expression programs, and how these neuro-cancer interactions evolve across tumor types.