Autophagy inhibition prevents lymphatic malformation progression to lymphangiosarcoma by decreasing osteopontin and Stat3 signaling.
Autophagy inhibition prevents lymphatic malformation progression to lymphangiosarcoma by decreasing osteopontin and Stat3 signaling.
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DOI：
10.1038/s41467-023-36562-5
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发表时间：
2023-02-22
影响因子：
16.6
通讯作者：
Guan, Jun-Lin
中科院分区：
文献类型：
--
作者：
Yang, Fuchun;Kalantari, Shiva;Ruan, Banzhan;Sun, Shaogang;Bian, Zhaoqun;Guan, Jun-Lin
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. Lymphatic malformation (LM) is a rare, non-malignant vascular abnormality that can progress to lymphangiosarcoma (LAS). The authors use genetic mouse models to show that autophagy inhibition blocks the progression of LM to LAS by decreasing osteopontin expression and Jak/Stat signalling.
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影响因子：
10.5
作者：
Chen S;Wang C;Yeo S;Liang CC;Okamoto T;Sun S;Wen J;Guan JL
通讯作者：
Guan JL
影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
20.3
作者：
Liu, Fei;Lee, Jae Y.;Guan, Jun-Lin
通讯作者：
Guan, Jun-Lin
婴儿血管瘤中的血管生成。
影响因子：
9.8
作者：
Boscolo E;Bischoff J
通讯作者：
Bischoff J