Modeling lymphangiosarcoma in mice

Sun, Shaogang; Guan, Jun‐Lin

doi:10.1080/15384101.2016.1176414

Cited by 2 publications

(1 citation statement)

References 6 publications

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“…In addition to OPN, our results showed down-regulations of other genes in several signaling pathways including PI3K-Akt signaling, ECM-receptor interaction and TNF signaling in vascular tumor cells after autophagy blockade. PI3K-Akt signaling has been well studied in vascular and other tumors, including our previous studies establishing a Tsc1 iΔEC mice model 17 , 55 , 56 . ECM-receptor interactions are also known to affect development and progression of different cancers 57 , 58 , although their potential roles in vascular tumor cells are not well understood.…”

Section: Discussionmentioning

confidence: 99%

Autophagy inhibition prevents lymphatic malformation progression to lymphangiosarcoma by decreasing osteopontin and Stat3 signaling

et al. 2023

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Lymphatic malformation (LM) is a vascular anomaly originating from lymphatic endothelial cells (ECs). While it mostly remains a benign disease, a fraction of LM patients progresses to malignant lymphangiosarcoma (LAS). However, very little is known about underlying mechanisms regulating LM malignant transformation to LAS. Here, we investigate the role of autophagy in LAS development by generating EC-specific conditional knockout of an essential autophagy gene Rb1cc1/FIP200 in Tsc1iΔEC mouse model for human LAS. We find that Fip200 deletion blocked LM progression to LAS without affecting LM development. We further show that inhibiting autophagy by genetical ablation of FIP200, Atg5 or Atg7, significantly inhibited LAS tumor cell proliferation in vitro and tumorigenicity in vivo. Transcriptional profiling of autophagy-deficient tumor cells and additional mechanistic analysis determine that autophagy plays a role in regulating Osteopontin expression and its down-stream Jak/Stat3 signaling in tumor cell proliferation and tumorigenicity. Lastly, we show that specifically disrupting FIP200 canonical autophagy function by knocking-in FIP200−4A mutant allele in Tsc1iΔEC mice blocked LM progression to LAS. These results demonstrate a role for autophagy in LAS development, suggesting new strategies for preventing and treating LAS.

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