Molecular and metabolic hallmarks of metastasis in triple negative breast cancer
- Author(s): Davis, Ryan Tevia
- Advisor(s): Lawson, Devon A
- et al.
Although metastasis remains the cause of most cancer-related mortality, mechanisms governing seeding in distal tissues are poorly understood. I hypothesized the initial stages of seeding at distal tissues (micrometastases) contain a unique transcriptome compared to primary tumor cells, enabling the identification of novel molecular targets to specifically block micrometastatic establishment. Here I established a robust method for identification of global transcriptomic changes in rare metastatic cells during seeding using single-cell RNA-sequencing and patient-derived xenograft (PDX) models of breast cancer. I found that both primary tumors and micrometastases display transcriptional heterogeneity, but micrometastases harbor a distinct transcriptome program conserved across PDX models that is highly predictive of poor survival in patients. Pathway analysis revealed mitochondrial oxidative phosphorylation (OXPHOS) as the top pathway upregulated in micrometastases, in contrast to higher levels of glycolytic enzymes in primary tumor cells, which was corroborated by flow cytometric and metabolomic analyses. Pharmacological inhibition of OXPHOS dramatically attenuated metastatic seeding in the lungs, which demonstrates the functional importance of OXPHOS in metastasis and highlights its potential as a therapeutic target to prevent metastatic spread in breast cancer patients.