Targeting WASp using Wiskostatin-gold nanoparticles
Mentor: Darrell J. Irvine, PhD (Massachusetts Institute of Technology)
Primary tumor progression is enhanced by inflammation of the lungs. When inflamed, the lungs are a central location for neutrophil recruitment and subsequent dissemination into protease granules. In order to reach the inflamed lungs, neutrophils must cross endothelial cells that form a monolayer within the lumen of the blood vessels. Unfortunately, the blood vessel wall is a large barrier when it comes to delivering nanoparticles (NPs) to the inflamed spot. Neutrophils, however, are capable of migrating through the bloodstream, to the alveoli, passing through endothelial and epithelial barriers on their way and eventually landing in distal lung airspaces. This neutrophil transmigration pathway proves a promising route for NP delivery to the lungs via neutrophil-encapsulated NPs. Specifically, gold NPs filled with the drug Wiskostatin will be created and encapsulated by neutrophils ex-vivo. They will then be injected into mice with a melanoma model and mice with a breast cancer model, where they will carry out their normal immune response duties and migrate towards the lungs. Wiskostatin is an inhibitor of the Wiskott-Aldrich Syndrome Protein (WASp), a protein expressed on neutrophils and other immune cells. WASp helps support migration of tumor-associated macrophages (TAMs) to cancer cells and production of epidermal growth factor (EGF), which are both processes that enhance primary tumor metastasis. We predict that WASp deficiency may decrease the interaction between TAMs and cancer cells and ultimately decrease tumor metastasis to secondary organs.
Lungs extracted from wildtype mice with MC38 (colon carcinoma) and B16F1 (mild form of melanoma) show more tumor invasion than lungs extracted from WASp-deficient mice, leading to the hypothesis that loss of WASp protects against migration of primary tumors into secondary organs. Source: Dr. Sudha Kumari, Irvine Lab, Koch Institute for Integrative Cancer Research at MIT Source: