INTERSTITIAL FLOWS MODULATE BREAST TUMOR CELL INVASION USING A 3D MICROFLUIDIC MODEL

Abstract

Tumor cell invasion through the extracellular matrix (ECM) is a critical step in the cancer metastatic cascade. Along the way from primary tumor to a distant metastatic site, tumor cells interact actively with the microenvironment either via biophysical or biochemical signals. It is now indisputable that the tumor microenvironment (TME) is as important as the genetic makeup of the tumor in regulating tumor invasion. To date, roles of biophysical cues within the TME, apart from matrix stiffness and architecture, in tumor invasion are poorly understood. Interstitial flows (IFs) are ubiquitous in maintaining tissue homeostasis in living systems, and are known to be elevated in malignant tumors due to the abnormal vasculature developed within the tumor. My dissertation focuses on revealing roles of IFs in breast tumor cell invasion using a newly developed 3D microfluidic platform and optical imaging. This dissertation contains four main parts. First, I reviewed current understanding on the subject of TME in tumor invasion. Second, I presented work on the development of a microfluidic platform that provided well defined IFs to cells or spheroids embedded within a type I collagen matrix. Third, I studied roles of IFs in modulating invasion characteristics of single breast tumor cells (MDA-MB-231 cell line). I found that IFs carried away the cell-secreted adhesion molecules, fibronectin, and subsequently promoted amoeboid over mesenchymal cell morphology and motility. Most importantly, IFs inhibited tumor cells’ ability to spread. Fourth, I studied roles of IFs in tumor spheroid invasion. For mono-culture spheroid (MDA-MB-231 cells supplemented with Matrigel), IFs inhibited tumor cell invasion. For co-culture tumor spheroids made of 1:1 mixture of malignant and non-tumorigenic epithelial cells, IFs promoted tumor cell invasion via downregulating cell-cell adhesion E-cadherin of non-tumorigenic cells. In summary, my work revealed that IFs inhibited tumor cell invasion in both single cell and mono-culture spheroid models via modulating cell-ECM adhesion. In contrast, IFs promoted tumor cell invasion in the co-culture spheroid model via downregulating cell-cell adhesion of the non-tumorigenic cells. My work highlighted the importance of biophysical parameter, IF, in regulating cell-ECM and cell-cell adhesion, and consequently modulating tumor invasion.