Investigation of Physical Constriction on Cancer Stem Cells

SUMMARY ABSTRACT: Cancer stem cells (CSCs) are a small population of cancer cells that are typically quiescent, but capable of self- renewal and tumor initiation. Non-CSCs, which make up the majority of the cancer cell population, are cells that are constantly dividing. Since CSCs are non-dividing, they are resistant to standard chemotherapy and radiation therapy, which only target actively dividing cells. Persistence of CSCs after therapy can thus result in disease relapse. Importantly, our recent work showed that programs of stemness are activated in tumor cells as they disseminate from primary tumors. Therefore, understanding what influences the formation of disseminating CSCs may provide new potential targets for therapeutic interventions of metastasis. Metastasis is a multi-step process and, in each step, disseminating tumor cells (DTCs) encounter different physical constrictions (e.g., physical confinement, solid stress, matrix stiffness, interstitial fluid pressure, and shear stress) that may affect their behavior. Recent reports in the literature indicate that one pathway for induction of programs of stemness is through the YAP/TAZ mechanotransduction signaling pathway, indicating that physical forces may, in part, be responsible for the induction of stemness in DTCs. This project will investigate the role physical constriction plays in stem cell induction by modelling the different physical constrictions that DTCs experience as they disseminate from primary tumors. This project will draw upon engineering and biological sciences to combine a unique, validated, fluorescent biosensor for stemness with advanced microfabricated microfluidic in vitro assays, and state-of-the-art intravital imaging of the live murine lung. We propose to use this combination to study the influence of physical forces on the selection, induction, and/or sustainment of metastasizing cancer stem cells, and evaluate their retention, survival, and extravasation efficiency in the in vivo lung.