Abstract 1831: Role of autophagy in lymphangiosarcoma initiation and progression

Abstract

Abstract Lymphangiosarcoma is a rare malignant vascular tumor which is formed from aberrant proliferation of endothelial cells (ECs). We previously established a vascular tumor mouse model by conditional knockout of Tsc1 gene in ECs and revealed that hyper-activated mTORC1 and increased VEGF autocrine are required for lymphangiosarcoma development and progression. However, we also found that there are other unknown factors which contribute to vascular tumor development besides mTORC1 hyper-activation. Autophagy has been shown to play an important role in tumor initiation and progression. However, the role of autophagy in mTORC1-dependent vascular tumor development is unclear. In this study, we studied the potential role and mechanism of autophagy in promoting lymphangiosarcoma development. FIP200 (FAK family interacting protein of 200 kDa) was identified as an essential autophagy gene, which was shown to play a key role in breast cancer development and progression. By crossing Tsc1f/f, Scl-Cre mice with Fip200f/f mice, we generated Tsc1/Fip200 double cKO mice. We found that Fip200 deletion blocked lymphangiosarcoma development induced by mTORC1 hyper-activation in mice. We established an immortalized lymphangiosarcoma cell line named Tsc1ΔEC from Tsc1 cKO mice and examined their growth in xenograft transplant models following CRISPR-Cas9 knockout of Fip200, Atg5 or Atg7 in Tsc1ΔEC cells. Our data showed that KO of each of these autophagy genes impaired vascular tumor growth in nude mice. Mechanistically, we found that Fip200 KO suppressed mTORC1 signaling activation under glucose starvation condition. In addition, we found that both Fip200 KO and lipase inhibitor Orlistat treatment in Tsc1ΔEC inhibited mitochondria respiration and decreased ATP content by seahorse assay. We also found that deletion of Fip200, Atg5, Atg7 or LAL in Tsc1ΔEC blocked lipid droplets (LDs) degradation and decreased glycerol release. Collectively, our data suggest that autophagy is required for lymphangiosarcoma initiation and progression through mTORC1 hyper-activation maintenance under stress conditions and supplying energy consumption by regulating lipid metabolism. Note: This abstract was not presented at the meeting. Citation Format: Fuchun Yang, Shaogang Sun, Jun-Lin Guan. Role of autophagy in lymphangiosarcoma initiation and progression [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 1831.