Mechanisms of NF1+/- Myeloid Cell Function in MPNSTs
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with poor prognosis. Approximately 8 to13% of neurofibromatosis type 1 (NF1) patients will develop MPNSTs in their lifetime, and new treatment options are desperately needed. We have recently identified a role for specific immune cells in MPSNT formation using genetically engineered mouse models, and we also discovered an NF1-dependent enrichment of these cells in patient MPNSTs (Dodd, et al., Cancer Research, 2017). We determined that these immune cells are mast cells and immature monocytes. Both are known to play important roles in several manifestations of NF1, but neither has been extensively studied in MPNSTs. Our recent findings underscore the importance of mast cells and monocytes in MPNST biology, and further work can uncover molecular mechanisms and targets that are driving MPNST growth. The main objective of this proposal is to uncover the mechanisms driving mast cell and monocyte function in NF1-associated MPNSTs, with an emphasis on identifying translational approaches that will improve treatment response. We hypothesize that NF1 +/- mast cells and/or monocytes can accelerate MPNST growth through distinct molecular signals that modify the surrounding tumor microenvironment to influence tumor formation. We will test this hypothesis with two independent aims in our mouse models. In Aim 1, we will determine the role of mast cells and monocytes in MPNSTs by generating tumors in mice with genetic disruptions in these cellular populations. In Aim 2, we will define and validate the molecular signals that influence mast cell and monocyte recruitment to the tumor. Importantly, this finding is specific to MPNSTs that occur in NF1 patients and represents a unique feature of NF1-releated biology. Using sophisticated mouse models, we will determine whether myeloid cells or their cytokines will be useful therapeutic targets. This proposal will use innovative CRISPR/Cas9 technology that allows us to model tumor biology in unique ways that facilitate rapid screening of multiple gene mutations in mice at a fraction of the cost and time required for genetically engineered models. If successful, this proposal could show that inhibiting specific molecules in the immune system will slow the growth of MPNSTs. Agents targeting immune cell infiltration or cytokine production have shown promise in other cancers, and the findings from this proposal will provide a foundation for clinical trials in neurofibromatosis patients. During the next decade, we believe these studies will uncover and validate novel pathways that can be harnessed to change treatment paradigms for NF1 patients with MPNSTs. In summary, this proposed research will greatly advance NF1 research by improving our understanding of key immune cells in MPNST biology and validating new cellular targets that can improve NF1 patient care and outcome.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810174
Entities
People
- Rebecca D Dodd
Organizations
- United States Army
- University of Iowa