Elucidating the Role of Mechanics and Lymphatic Pumping on Lymphovascular Space Invasion Using a Lympho-vascularized Breast-Skin Platform

University Of Texas At Austin, Austin TX

Investigators

Abstract

Metastasis is a complex series of cell migration events that involve multiple interactions with other cells, tissues, and blood and lymphatic vessels - causing the mechanisms to be unclear and treatments to be ineffective. Elucidating this complex cascade is impossible with current cell culture-based systems and cost prohibitive with animal models. Multi-tissue on-a-chip platforms (MTCPs) that possess integrated blood and lymphatics within a primary tissue (e.g. breast) and a secondary site (e.g. skin) while also replicating the biomechanical properties of these tissues would have tremendous value for uncovering cell migratory patterns of cancer metastasis, and ultimately impact drug development, personalized medicine, disease etiology, and toxicology. This project’s objective is to create a MTCP Breast-Skin platform with blood and lymphatic vasculature integrated within each tissue and connected seamlessly across tissues. The Breast-Skin platform will be utilized to determine the role of tissue properties, immune cells, and vessel flow dynamics in tumor cell metastasis. This work is a high-risk, high-reward endeavor, providing an invaluable tool for dissecting the metastatic process which will generate functional signaling and therapeutic targets for treatment of a wide array of aggressive and metastatic diseases. The project will enable the PI to provide unique tiered teaching and mentoring opportunities in which graduate and undergraduate students will expand their understanding of microfluidics fabrication and serve as role models for elementary school students through a newly created tissue instructional module for an existing outreach program at The University of Texas at Austin Longhorn Engineering Summer Camp. Metastatic cancer spread is a highly complex series of events involving multiple tissues, organs, and cellular interactions. Several clinical phenomena have been correlated with metastasis and poor patient outcomes, but their underlying mechanisms remain difficult to determine. Three such phenomena are of interest because of their significant clinical presentations in breast cancer: 1) lymphovascular space invasion (LVSI) – tumor clusters (emboli) within blood and lymphatic vasculature in the primary tumor, 2) dermal lymphatic invasion (DLI) – tumor emboli within the lymphatic vessels of the nearby skin tissue, and 3) skin metastasis. Existing in vitro systems lack the multi-tissue and lymphovascular complexity needed to model these events. In vivo models, while available, are not amenable to mechanistic studies or pharmacological screening because of the sheer number of animals required for such experiments. Therefore, there is a critical need for experimental models that can faithfully capture relevant metastatic phenomena. This need will be addressed by developing a multi-tissue on-a-chip Breast-Skin platform with functional blood and lymphatic vessels that are seamlessly connected to study the spatial and temporal process of LVSI, DLI, and skin metastasis. The central hypothesis is that the cross-talk between the extracellular matrix (ECM), macrophages, and vessel microenvironment provides synergistic cues to drive LVSI and DLI. This hypothesis will be tested in the Breast-Skin platform with the following project objectives: 1) Develop and validate the first Breast-Skin in vitro platform for modeling LVSI and DLI in breast cancer, 2) Determine the role of ECM features and macrophages in LVSI and DLI formation, and 3) Define the contribution of vessel fluid dynamics to LVSI and DLI formation. The project represents a significant breakthrough in the development of a unique Breast-Skin platform to study the spatial and temporal process of LVSI, DLI, and skin metastasis for the first time in a high-throughput and controllable manner. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.