Lymphangiosarcoma is a rare malignant vascular tumor which is formed from aberrant proliferation of endothelial cells (ECs). We previously established an endogenous mouse model of lymphangiosarcoma by conditional knockout of Tsc1 gene in ECs and revealed that hyper-activated mTORC1 is required for the vascular tumor development and progression through increased VEGF autocrine signaling. Using this model, we investigated the role of an essential autophagy gene FIP200 (FAK family interacting protein of 200 kDa) and its canonical autophagy function in lymphangiosarcoma development and progression by generating a FIP200 knockout (designated as Tsc1/Fip200 2cKO mice) or introducing a knockin allele that specifically blocks its canonical autophagy function (designated as Tsc1/Fip200 cKI mice) in combination with Tsc1 cKO in this study. We found that while both Tsc1/Fip200 cKO and Tsc1/Fip200 cKI mice exhibited lymph edema phenotype as Tsc1 cKO mice, they did not develop lymphangiosarcoma, suggesting that autophagy is required for lymphangiosarcom formation. Consistent with the above results, we also found that CRISPR-Cas9 mediated Fip200 KO in an immortalized vascular tumor cell line Tsc1ΔEC from Tsc1 cKO mice blocked their ability to grow tumors in xenograft transplants. Mechanistically, we found that autophagy was required for maintaining mTORC1 hyper-activation under nutrient stress condition. Moreover, the impaired lipophagy by Fip200 knockout affected lipid catabolism under glucose free condition and thus reduced the substrate for fatty acid oxidation (FAO). Our data showed that Fip200, Atg5 or Atg7 ablation in Tsc1ΔEC inhibited mitochondria respiration and decreased ATP contents as measured by Seahorse assays. Either lipase inhibitor Orlistat or carnitine palmitoyltransferase-1 (Cpt1) inhibitor Etomoxir treatment decreased Tsc1ΔEC mitochondria respiration and ATP production. Collectively, our data suggested that autophagy is required for lymphangiosarcoma initiation and progression by modulating FAO to supply cellular energy under stress for sustaining mTORC1 hyper-activation for tumor growth.

Citation Format: Fuchun Yang, Michael Haas, Jun-Lin Guan. The role of autophagy in lymphangiosarcoma development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2468.