Paracrine Pathways Causal in Growth and Invasion of Neurofibromas: Contributions of Cellular Microenvironment
Abstract
Why is it important to study neurofibromatosis type 1 plexiform neurofibromas (NF1 PNs)? Type 1 Neurofibromatosis (NF1) is one of the most common genetic and neurological disorders, occurring in the population with an incidence of approximately one in 3,000 persons. Neurofibromas usually start in early childhood and grow in size and number. Up to half of children with NF1 have plexiform neurofibromas (PNs). PNs grow very fast, invade surrounding structures, and can cause physical compression of nerves and vital organs. Surgical removal is the primary current treatment option, which can cause problems such as paralysis because the tumors grow along and around nerves. Moreover, regrowth of tumors is often observed because the tumors invade surrounding tissues and so are difficult for the surgeon to remove tumors completely. A recently approved drug, Selumetinib, is for NF1 PNs that cannot be removed by surgery. However, Selumetinib does not reduce tumor growth completely. Thus, there is a need to find drugs to prevent the growth and/or invasion of NF1 PNs before nerves and vital organs are compressed by excessive growth of tumors. Why will we study the contributions of the cellular microenvironment to the growth and invasion of NF1 PNs? Neurofibromas are made up of abnormal Schwann cells, i.e., tumor cells, and other cell types in the surrounding tumor microenvironment. The NF1 PN tumor microenvironment includes cellular (e.g., neuronal axons, fibroblasts, infiltrating inflammatory cells such as mast cells and macrophages) and non-cellular (e.g., acidity and low oxygen) microenvironments. The cellular microenvironment is thought to play a critical role in formation of NF1 PNs. However, little is known about its contribution in mediating the growth and invasion of NF1 PNs. Thus, we predict that understanding the roles of the cellular microenvironment in NF1 PN will identify new potential targets for treatment of patients. How will we identify new therapeutic targets to prevent the growth and invasion of NF1 PNs? Three-dimensional (3D) cell culture models, rather than conventional 2D cell cultures on petri dishes, allow cells to grow in architecture called extracellular matrix similar to that in humans. Thus, 3D culture models are recognized as useful and reliable for screening drugs before testing in animals or humans. Moreover, 3D culture models provide benefits relative to animal models, which are complex, very expensive, and hard to use for testing multiple drug combinations at a time. Our laboratory has in hand novel and robust 3D/4D (3D in real-time) culture models of NF1 PNs comprised of tumor cells and patient-derived fibroblasts, a major component of the cellular microenvironment, that will be used for drug screening. We will further mimic the complex tumor structures present in NF1 PN patients by adding engineered models of neuronal nerves into the 3D/4D cultures of tumor cells and fibroblasts. To evaluate the growth and invasion of NF1 PNs, we will assess and quantify effects by imaging of live tumors as they grow and invade in cultures. Moreover, we will identify factors secreted into the microenvironment of NF1 PNs that mediate their growth and invasion and may be targeted to prevent growth and invasion. We will use our patented culture chambers (Patent: US 10,227,556 B2) to collect secreted factors in 3D cultures of NF1 PNs for analysis and to test the ability of drugs to prevent the growth and invasion of NF1 PNs. Moreover, we will verify that our candidate molecules are present in NF1 PN tissues from mouse models and patients. We expect that this study should deliver new tools for the study and treatment of NF1 PNs, potentially increasing patient quality-of-life and survival.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210564
Entities
People
- Kyungmin Ji
Organizations
- Henry Ford Health
- United States Army