KRAS mutant–driven SUMOylation controls extracellular vesicle transmission to trigger lymphangiogenesis in pancreatic cancer
Yuming Luo, Zhihua Li, Yao Kong, Wang He, Hanhao Zheng, Mingjie An, Yan Lin, Dingwen Zhang, Jiabin Yang, Yue Zhao, Changhao Chen, Rufu Chen
Yuming Luo, Zhihua Li, Yao Kong, Wang He, Hanhao Zheng, Mingjie An, Yan Lin, Dingwen Zhang, Jiabin Yang, Yue Zhao, Changhao Chen, Rufu Chen
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Research Article Oncology

KRAS mutant–driven SUMOylation controls extracellular vesicle transmission to trigger lymphangiogenesis in pancreatic cancer

Abstract

Lymph node (LN) metastasis occurs frequently in pancreatic ductal adenocarcinoma (PDAC) and predicts poor prognosis for patients. The KRASG12D mutation confers an aggressive PDAC phenotype that is susceptible to lymphatic dissemination. However, the regulatory mechanism underlying KRASG12D mutation–driven LN metastasis in PDAC remains unclear. Herein, we found that PDAC with the KRASG12D mutation (KRASG12D PDAC) sustained extracellular vesicle–mediated (EV-mediated) transmission of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) in a SUMOylation-dependent manner and promoted lymphangiogenesis and LN metastasis in vitro and in vivo. Mechanistically, hnRNPA1 bound with SUMO2 at the lysine 113 residue via KRASG12D-induced hyperactivation of SUMOylation, which enabled its interaction with TSG101 to enhance hnRNPA1 packaging and transmission via EVs. Subsequently, SUMOylation induced EV-packaged-hnRNPA1 anchoring to the adenylate- and uridylate-rich elements of PROX1 in lymphatic endothelial cells, thus stabilizing PROX1 mRNA. Importantly, impeding SUMOylation of EV-packaged hnRNPA1 dramatically inhibited LN metastasis of KRASG12D PDAC in a genetically engineered KrasG12D/+ Trp53R172H/+ Pdx-1-Cre (KPC) mouse model. Our findings highlight the mechanism by which KRAS mutant–driven SUMOylation triggers EV-packaged hnRNPA1 transmission to promote lymphangiogenesis and LN metastasis, shedding light on the potential application of hnRNPA1 as a therapeutic target in patients with KRASG12D PDAC.

Authors

Yuming Luo, Zhihua Li, Yao Kong, Wang He, Hanhao Zheng, Mingjie An, Yan Lin, Dingwen Zhang, Jiabin Yang, Yue Zhao, Changhao Chen, Rufu Chen

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Figure 6

SUMOylated hnRNPA1 is packaged into EVs by interacting with TSG101.

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SUMOylated hnRNPA1 is packaged into EVs by interacting with TSG101. (A a...
(A and B) Co-IP assay followed by silver staining (A) and Western blotting analysis (B) for detecting SUMOylated-hnRNPA1–interacting proteins in PANC-1 cells with or without SAE1 knockdown. IB, immunoblot. (C) Co‑IP assays analyzing the interaction of hnRNPA1 and TSG101 mediated by SAE1-induced SUMOylation on hnRNPA1. (D) Representative immunofluorescence images of hnRNPA1 and TSG101 colocalization in PDAC cells. Scale bar: 5 μm. (E and F) Western blotting analysis of hnRNPA1 expression in PANC-1 cells (E) and corresponding EVs (F) after TSG101 knockdown. (G and H) Representative images and quantification of tube formation and migration of HLECs treated with indicated EVs. Scale bars: 100 μm. One-way ANOVA followed by Dunnett’s test was used. Data are presented as mean ± SD of 3 independent experiments. **P < 0.01.