Interrogating Tumor-Immune-Neuron Cross Talk at Single-Cell Resolution in a Panel of Novel Somatic Transgenic NF1 Tumor Models
Abstract
We now know an incredible amount about the genetic mutations associated with NF1 glioma. However, there is an urgent need for representative genetically engineered preclinical disease models that reflect these combinations of mutations, due to a lack of human cell lines for NF1-associated glioma. In addition, mouse models provide the opportunity to interrogate the role of neuroimmune crosstalk in the pathogenesis of glioma. Inhibiting this crosstalk is one of the potential exciting therapeutic approaches for NF1 as preclinical studies have identified critical pathways involved in the neuroimmune regulation of Nf1 optic pathway glioma. Current mouse models of brain gliomas are a mix of mutations that are either not prevalent in NF1-associated cases, or do not reflect the most common mutation signature. Specifically, combined loss of the genes Cdkn2a, Trp53, and Atrx (or Fgf1 amplification in the case of low-grade tumors). In addition, none of these models incorporate the inherited Nf1 mutation. Our approach is to generate novel NF1 glioma (low-grade and high-grade) models using our new state-of-the-art genetic engineering approaches for tumor modeling in mice, by precisely targeting each of the above mutations and NF1 patient derived inherited Nf1 mutations simultaneously (Breunig and Gutmann laboratories). In addition, we will test whether the neuron-immune axis/molecules that drive disease progression in NF1 optic pathway gliomas is also required for the progression of NF1-gliomas in the brain (Breunig and Pan laboratories). Completion of the novel experiments outlined in this proposal will directly address the FY22 NFRP areas of emphasis: Heterogeneity of NF-related tumors and Target identification, drug discovery. Benefits and Risks: Deriving new cancer models can be time-consuming and fraught with challenges. However, our published approach has demonstrated the ability to accurately model multiple tumor types—even when assessing cell-by-cell with human tumors. Further, we can mix and match additional mutations in the future to expand to the less common tumor signature mutations, allowing for precision patient disease avatars. We will thus use these mice as patient avatars for the ongoing clinical trial by employing the same therapeutics as are used in the trial. Using survival analysis, we will assess the predictive nature of these models for therapeutic testing. In addition, using single-cell approaches, we will directly compare the mouse and human tumors on a cell-by-cell basis to assess their fidelity in recapitulating human tumors. By credentialing our models against current frontline and experimental therapies, we have designed our proposal to be of maximal benefit to patients with NF1. Specifically, if our models our predictive, they can be used to assess safety and efficacy of combinatorial approaches and novel therapeutic interventions (e.g., targeting the neuron-immune axis) that would take years to decades to similarly complete in the clinical trial setting—all while patients with NF1 glioma continue to succumb to the disease. Our proposed models can additionally be used to determine tumor-intrinsic and extrinsic mechanisms of gliomagenesis in NF1 and derive new targets for therapeutic intervention. Last, our approach is relatively cheap, simple, and faster than the traditional engineered mouse models. We have previously made our tools available to the scientific community (e.g., through open access repositories such as Addgene) and will continue to do so, multiplying the potential for impact in the fight against NF1. There are no clinical risks to patients, and risks to animals will be minimized by following federal and institutional regulations of rodent care. Taken together, we hope that these preclinical studies will lead to a new generation of patient NF1 disease models and new targeted therapeutic interventions with minimal side effects for the family members of the milit
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310269
Entities
People
- Joshua J. Breunig
Organizations
- Cedars-Sinai Medical Center
- United States Army