Gradient Hydrogels for Identifying Highly Invasive Pancreatic Cancer Cells
Abstract
Focus Area: Understanding the events that promote pancreatic cancer metastasis Pancreatic ductal adenocarcinoma (PDAC) is highly metastatic. The overall survival rate of PDAC is very low, especially in patients with metastatic PDAC, in which the 5-year survival rate is a dismal 3%. Hence, understanding how PDAC cells move to other parts of the body will benefit the identification of novel therapeutic targets. Tumor tissues are highly complex, often having properties that are vastly different in different areas of the tissues. For example, the periphery of solid tumor is more fibrotic and contains more proteins (e.g., fibronectin) than the core. Consequently, tumor peripheral area is usually harder than that in the core. These gradients are believed to promote cell invasion and migration toward blood/lymphatic vessels for their dissemination to the distant organs. It is apparent that engineering devices are needed to create complex gradients and do a better job of modeling metastatic events. Existing engineering tools have achieved various levels of success in generating gradients. While prior efforts have facilitated the studies of gradient-induced cell migration, they often involved delicate device fabrication and lack adaptability to generate multiple gradients in the same device. Because of the sophisticated designs in the existing gradient material systems, it is also challenging to study a wide range of gradients implicated in cell migration/invasion. The objective of this project is to design biomaterials that present multiple physical and chemical gradients observed in the tumor tissue (e.g., protein and hardness gradients) and study their effects on directional migration and invasion of pancreatic cancer cells. We will employ 3D bioprinting, polymers, and simple diffusion to create cancer cell containing hydrogels that also exhibit gradients of molecules and hardness that implicate cancer cell migration. To the best of our knowledge, this will be the first cell-containing hydrogel with on-demand generation of multiple physicochemical gradients, which will induce directional cell migration and allow us to isolate cell populations with high migratory and invasive potential -- the cells that would likely be responsible for metastasis. The impact of our gradient hydrogel is twofold: (1) it will allow multi-faceted evaluation of directional cell migration, which usually involves crosstalk of several signaling pathways, and (2) it will permit identification/sorting of highly migratory cancer cells using physicochemical gradients. Migratory tumor cells are the cause of cancer metastasis. Hence, sorting a subset of cancer cells that are particularly sensitive to multiple physicochemical gradients will improve the chances of success in identifying molecular targets against cancer metastasis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210864
Entities
People
- Chien-Chi Lin
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army