Defining the Role of Macropinocytosis in NF-Mutant Tumors
Abstract
Through basic science studies we have discovered that an important unrecognized function of the NF2 tumor suppressor protein, Merlin, is to “quiet” the surface of the cell; as such, the surface of NF2-mutant cells is very excitable and turbulent. One important and unexpected consequence of this is that NF2-mutant tumor cells are easily excited by growth factors and, in response, gulp up fluids from their environment and internalize them as if they were captured by a breaking wave. This process, known as macropinocytosis, is used by some tumor cells to gulp up nutrients in the environment; the turbulent waves on the surface of Nf2-/- cells also function like moving satellite dishes that concentrate growth factor signals and enable cells to respond to weak signals that they normally wouldn’t respond to. Our preliminary studies suggest that NF2-mutant cells of multiple types, including Schwann cells and meningioma cells, excel at macropinocytosis and can respond excitedly to growth factors that they normally might not detect. We hypothesize that this ability allows NF2-mutant Schwann cells to survive and grow outside of the normal nerve milieu and drive tumor heterogeneity by enabling cells to adapt to alternative growth factors from outside their normal environment. We propose that a second advantage conferred by this “macropinocytic proficiency” is that Nf2-/- cells can gulp up extra nutrients, primarily cholesterol and other lipids, from their environment, which further fuels their inappropriate growth factor responsiveness. Notably, macropinocytosis can also be triggered by activation of the Ras oncoprotein, which is normally kept inactive by the NF1 tumor suppressor; indeed, we found that NF1-mutant Schwann cells are also very good at macropinocytosis, although they carry it out differently than Nf2-/- cells. The goals of this proposal are to test the hypothesis that the macropinocytic proficiency of NF2- and NF1-deficient cells allows them to adapt and proliferate outside of their normal environment. We will examine the molecular basis of this, identify biomarkers of specific growth factor responses, and test several specific ways to block this advantage as novel therapeutic strategies in preclinical studies carried out in cultured NF-mutant schwannoma, meningioma, and MPNST cells and in Nf2-mutant schwannoma mouse models. This work will ultimately benefit both NF2 and NF1 patients, as it will identify novel causes, biomarkers, and therapeutic strategies for multiple types of NF2- and NF1-mutant tumors.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910156
Entities
People
- Andrea I McClatchey
Organizations
- Massachusetts General Hospital
- United States Army