Dr. Chien-Chi Lin, Thomas J. Linnemeier Guidant Foundation Endowed Chair & Professor of Biomedical Engineering in the School of Engineering and Technology, IUPUI, has recently received two federal grants, a 4-year NIH R01 grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and a 3-year pancreatic cancer research program (PCARP) Ideal Development Award from the Department of Defense (DoD). The R01 grant provides more than $1.9 million over four years, and the DoD PCARP award offers $575K over three years.
The R01 grant is the most sought-after long-term grant mechanism from the NIH. In this grant, Dr. Lin and his team aim to create engineered hydrogels with precisely tunable physicochemical properties to generate pancreatic organoids from human-induced pluripotent stem cells (hiPSC). hiPSCs are cells that can be differentiated/matured to all types of cells in the body and therefore provide an invaluable cell source for basic research and therapeutic applications. While recent years have witnessed breakthroughs in lineage-specific differentiation of hiPSC, the effect of matrix stiffness, viscoelasticity, and cell surface receptor activation during pancreatic organoid (mini multi-cellular structure that can mimic the function and construction of a mature organ) development remains largely unexplored. Current three-dimensional (3D) matrices for hiPSC culture and differentiation do not provide sufficient controls over matrix biophysical properties and biochemical motifs. Additionally, no prior work has employed chemically defined hydrogels to study the effect of matrix mechanics and cell-adhesive ligand on the development of hiPSC-derived pancreatic organoids, which can be used to study pancreatic cancer and other digestive and metabolic diseases such as diabetes.
The DoD PCARP Idea Development Award is highly competitive, and in this award, Dr. Lin will collaborate with Dr. Melissa Fishel from IU School of Medicine to design biomaterials that recapitulate multiple physicochemical gradients observed in the pancreatic tumor stroma and study their effects on directional migration and invasion (i.e., chemotaxis, haptotaxis, durotaxis) of pancreatic cancer cells (PCCs). Pancreatic ductal adenocarcinoma (PDAC) is highly metastatic. In patients with metastatic PDAC, the 5-year survival rate is a dismal 3%. Hence, understanding the mechanisms by which PDAC cells migrate and invade the stroma will benefit the identification of novel therapeutic targets. Tumor stromal tissues exhibit complex and heterogeneous properties, including the presence of multiple physicochemical gradients. These physical and biochemical gradients are believed to promote cell invasion and migration toward blood/lymphatic vessels for their dissemination to distant areas. While prior efforts have facilitated the studies of directional cell migration, they often involved delicate device fabrication and lacked adaptability to generate multiple physicochemical gradients. Because of the sophisticated designs in the existing gradient hydrogel systems, it is also challenging to rapidly screen a wide range of physicochemical gradients implicated in cell migration/invasion. Therefore, this project aims to integrate orthogonal click chemistry and fabrication to identify factors governing aggressive migration and invasion of pancreatic cancer cells.
Dr. Lin works in IUPUI's BME department, where he is applying his expertise in biomaterials and tissue engineering to address many challenging biomedical problems, including pancreatic cancer and diabetes. "Our research focuses on designing multifunctional polymeric biomaterials, including hydrogels and nanoparticles for releasing therapeutically relevant agents and delivering adult, stem, and progenitor cells for tissue engineering and regenerative medicine applications," said Dr. Lin. "In this project, we will study the role of mechanical matrix properties, including stiffness and viscoelasticity, on pancreatic progenitor differentiation. We will also identify the role of cell surface receptor activation on pancreatic ductal/acinar cell specification. In the long-term, this project will produce a hydrogel platform to advance the use of chemically-defined matrices for organoid development and tissue regeneration applications".
“Dr. Lin’s sustained success in garnering extramural support from highly competitive sponsors for his world-class research exemplifies our School’s research mission to compete and succeed at the highest levels," said Dr. Russomanno, dean of the Purdue School of Engineering and Technology at IUPUI.
Dr. Wallace, Chair of the BME department, commented on Lin’s achievements by saying, "Being funded by R01s from 2 different NIH institutes at the same time is remarkable and speaks to the breadth of Dr. Lin’s research program and the potential positive impact this work can have to better human health outcomes."
Dr. Lin is also a member of the Indiana University Simon Comprehensive Cancer Center and Center for Diabetes and Metabolic Diseases. Since 2011, Dr. Lin's research has been supported continuously by grants from federal agencies, including another ongoing R01 grant from the National Cancer Institute (NCI) of the NIH, a CAREER award from the National Science Foundation, and several other federal, foundation, and industry grants.
