Abstract PR09: Modeling the tumor microenvironment in sarcoma: The impact on MPNST biology and chemotherapeutic response

Abstract

Abstract NF1 haploinsufficiency is a hallmark of neurofibromatosis Type 1 and is critical for neurofibroma development. The role of the supporting stroma (endothelial cells, immune cells, fibroblasts, etc.) in the development of patient neurofibromas is well established. However, the impact of NF1 haploinsufficiency on MPNST biology is less clear. Sporadic MPNSTs arise in patients with NF1 wild-type stroma (NF1 +/+), while NF1-associated MPNSTs arise in neurofibromatosis patients with NF1 haploinsufficient stroma (NF1 -/+). Patients with NF1-associated MPNSTs have worse outcome than patients with sporadic MPNSTs, but the cause of this difference is under debate. To define the impact of stromal genetics on tumor biology, we have developed unique mouse models that reflect the genetics of patient-associated MPNSTs. Using paired littermate mice, we model the genetic status of NF1 in the tumor microenvironment of different MPNST patient populations. We use Adenovirus-Cre injections to generate MPNSTs in NF1 Flox/Flox; CDKN2A Flox/Flox and NF1 Null/Flox; CDKN2A Flox/Flox paired littermate mice to model tumors from NF1 wild-type and NF1-assoicated patients, respectively. We find that NF1 haploinsufficiency (NF1 +/- stroma) accelerates tumor onset, which is accompanied by an increase in immune cells comprising CD11B+ cells, monocytes, and mast cells. Furthermore, mast cells are also enriched in human NF1-associated MPNSTs. We used these mouse models in a preclinical trial to examine how the tumor microenvironment influences response to multiagent chemotherapy and found that the stromal NF1 status does not impact the response of MPNSTs to chemotherapy. Taken together, these studies help clarify the role of the NF1 haploinsufficient tumor microenvironment in MPNSTs. This abstract is also being presented as Poster B15. Citation Format: Rebecca Dodd, Chang-Lung Lee, Mary Overton, Wesley Huang, William Eward, Davis Ingram, Diana Cordona, Alexander Lazar, David Kirsch. Modeling the tumor microenvironment in sarcoma: The impact on MPNST biology and chemotherapeutic response [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr PR09.