Abstract 4631: Modeling the vascular sarcoma spectrum with genetically engineered mice

Abstract

Abstract Angiosarcomas are highly aggressive vascular sarcomas with an extremely poor prognosis. Angiosarcomas can develop spontaneously or are associated with prior radiation, chronic lymphedema, or exposure to toxic chemicals such as vinyl chloride. Sequencing efforts have identified a number of genetic alterations in angiosarcoma, however the genetic drivers and actionable targets remain unclear. Despite the poor outcome for patients, there are limited resources for studying angiosarcoma, highlighting the need for genetic, in vivo models to better elucidate the underlying biology of the disease. In studying the role of DICER1 and microRNAs in mouse models of tumorigenesis, we found that Dicer1 deletion with aP2-Cre leads to aggressive and metastatic angiosarcoma development with 100% penetrance. ERK and S6 hyperphosphorylation in the aP2-Cre;Dicer1cKO (AD) tumors suggest Dicer1 loss results in activation of the RAS-MEK-ERK and mTOR pathways. To determine if direct activation of the these pathways could similarly transform aP2-Cre expressing cells we first interrogated the combination of oncogenic KrasG12D with Cdkn2a inactivation. We found that aP2-Cre;LSL-KrasG12D;Cdkn2acKO (AKC) mice rapidly develop angiosarcomas providing an accelerated model for assessing cooperating alleles and therapies. To activate the mTOR pathway we tested conditional Tsc1 deletion with aP2-Cre and found that all aP2-Cre;Tsc1cKO (AT) animals develop vascular tumors in the paws. In contrast to the AD and AKC tumors, AT tumors express markers of lymphatic endothelial cells such as PROX1. In addition, the tumors display a distinct nodular spindle cell-like morphology that is consistent with a low grade angiosarcoma resembling human kaposiform hemangioendotheliomas, a vascular tumor occurring predominantly in the extremities of infants. The distinct onset, growth kinetics, anatomic locations, and histologic presentation of the tumors from AD, AT, and AKC mice provide a mechanism to interrogate the drivers of angiosarcoma in less aggressive AT paw tumors and more aggressive AD and AKC tumors. Furthermore, the aP2-Cre driven mouse models provide a platform to study angiosarcoma initiation, progression, and metastasis for the identification of novel therapeutics to improve outcomes for this understudied and devastating disease. Citation Format: Jason A. Hanna, Casey G. Langdon, Matthew R. Garcia, David Finkelstein, Jerold E. Rehg, Mark E. Hatley. Modeling the vascular sarcoma spectrum with genetically engineered mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4631.