Project Name: Microfluidic-based Identification of Drivers of Tumor-initiating Cells
Breast cancer-related deaths will continue to rise if new steps in treatment are not taken. Recent studies have shown that tumor formation and cancer progression are driven by tumor-initiating cells (TICs, also known as cancer stem cells (CSCs)). TICs are a small subpopulation of the tumor that greatly contribute to treatment failure and promote disease recurrence due to their enhanced migration and resistance to commonly used chemotherapeutics (chemoresistance). Therefore, successful cancer treatment depends on effective targeting of TICs.
Our long-term goal is to identify the molecular drivers of TICs to discover new targets for cancer therapy. One of the major challenges currently facing TIC biology is the efficient isolation and recovery of TICs for study. Current techniques for isolating breast cancer TICs revolve around internal or cell surface markers. However, these techniques have several major setbacks including a lack of specificity for only TICs, and the fact that these markers do not directly correlate with TIC function or even patient prognosis and outcome. Therefore, there is an urgent need to improve techniques used to identify and isolate TICs for further study.
To address this deficiency, we have developed a device which functionally isolates TICs based upon their enhanced ability to migrate. Using our device, we have identified a unique set of migratory cells that have a greater tumor-initiating potential than matched non-migratory cells. One of the key differences between these cells is the decreased expression of phosphatidylserine decarboxylase (PISD) in migratory cells, which suggests PISD as a potential regulator of TICs. PISD is located within the mitochondria of cells, and consistent with this our preliminary results demonstrate that PISD regulates the energy and cellular metabolism of cells. We also found that increasing PISD expression reduces the TIC population in breast cancer cell lines, which suggests that PISD regulates TIC biology through mitochondria and metabolism.
The goals of this project are to:
1. Determine how PISD regulates TIC through effects on mitochondrial morphology
2. Elucidate the effects of PISD on metabolism as a mechanism to regulate TICs
Overall, this research will provide the foundation for mechanisms that drive TICs, and will also identify novel therapeutic options for patients with recurrent or metastatic disease.