UC Irvine

Metastasis is a major determinant of patient survival in cancer, yet the genetic and metabolic mechanisms underlying metastatic progression remain poorly understood. In our previous work, we identified PHLDA2, a gene not previously implicated in breast cancer metastasis, as a transcriptional marker of metastatic breast cancer. Analyzing patient datasets, we found this gene is more highly expressed in breast tumor tissue than normal tissue. This elevated expression is likely driven by methylation, as PHLDA2 is an imprinted gene, indicating a potential role for epigenetic regulation in its overactivation in cancer. Patient datasets revealed that high PHLDA2 expression is associated with reduced relapse-free and distal metastasis-free survival, underscoring its prognostic significance. Building on these findings, this thesis explores PHLDA2 as a driver of metastatic burden, demonstrating that it promotes breast cancer metastasis by restructuring the extracellular matrix and increasing vessel permeability, thereby reshaping the metastatic microenvironment. Additionally, to better study the metabolic processes driving aggressive cancer cell behavior at metastatic sites, I developed a single-cell metabolomics approach. This work identifies citrate as a potential metabolic drivers of cancer metastasis using a novel tool to study cancer metabolism at a single-cell resolution.