MVB Maturation Responsive to KRASG12D/TP53R175H Co‐mutations Fuels Extracellular Vesicle‐hypersecretion Phenotype to Aggravate Lymphangiogenesis and Lymphatic Metastasis
- 1Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University
- 2Sun Yat‐sen Memorial Hospital Sun Yat‐sen University
- 3The Eighth Affiliated Hospital of Sun Yat‐Sen University
Abstract
KRASG12D/TP53R175H mutations are hallmarks of malignant tumor progression and are associated with lymph node (LN) metastasis in solid tumor. Nevertheless, the mechanisms underlying KRASG12D/TP53R175H co‐mutation‐mediated LN metastasis remain unclear. Herein, we developed KRASG12D/TP53R175H mutation‐related orthotopic xenograft models and demonstrated that KRASG12D/TP53R175H co‐mutation promotes the lymphangiogenesis and LN metastasis. FUS is identified by next generation sequencing to be upregulated in tumor tissues harbouring KRASG12D/TP53R175H co‐mutation across multi‐center cohorts, wherein KRASG12D‐mediated phosphorylation of TP53R175H promotes FUS transcriptional activation. Functionally, FUS‐mediated extracellular vesicle (EV) promotes lymphangiogenesis and LN metastasis in vitro and in vivo. Mechanistically, upon KRASG12D/TP53R175H co ‑ mutation, FUS regulated circSCARNA10 biosynthesis and promotes EVs secretion by stabilizing RAB3B mRNA, leading to VEGFR3 transcription in lymphatic endothelial cells to trigger lymphangiogenesis and LN metastasis. Blockade of FUS inhibits LN metastasis in KrasG12D/+Trp53R172H/+Pdx‐1‐Cre (KPC) mice model. Clinically, detecting circSCARNA10 in serum‐EVs exhibited higher diagnostic efficiency compared with traditional biomarkers, carcinoembryonic antigen (CEA) and carbohydrate antigen 19‐9 (CA19‐9) in distinguishing LN metastasis. Collectively, we highlight the precise mechanisms by which KRASG12D/TP53R175H co‐mutation mediates EV secretion to trigger LN metastasis, providing a potential therapeutic target for KRASG12D/TP53R175H co‐mutation ‐ driven LN metastasis.
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BibTeX
@article{yang2026maturation,
title = {{MVB Maturation Responsive to KRASG12D/TP53R175H Co‐mutations Fuels Extracellular Vesicle‐hypersecretion Phenotype to Aggravate Lymphangiogenesis and Lymphatic Metastasis}},
author = {Jiabin Yang and Yuming Luo and Yu Zhou and Mingjie An and Mingrui Pang and Zhihua Li and Qingyu Xie and Hanhao Zheng and Zhou Fang and Yao Kong and Chao Yu and Yan Lin and Dingwen Zhang and Bingxin Cao and Haoming Zhong and Changhao Chen and Rufu Chen},
journal = {Journal of extracellular vesicles},
year = {2026},
month = oct,
doi = {10.1002/jev2.70383},
url = {https://europepmc.org/article/PMC/PMC13653645},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - MVB Maturation Responsive to KRASG12D/TP53R175H Co‐mutations Fuels Extracellular Vesicle‐hypersecretion Phenotype to Aggravate Lymphangiogenesis and Lymphatic Metastasis
AU - Jiabin Yang
AU - Yuming Luo
AU - Yu Zhou
AU - Mingjie An
AU - Mingrui Pang
AU - Zhihua Li
AU - Qingyu Xie
AU - Hanhao Zheng
AU - Zhou Fang
AU - Yao Kong
AU - Chao Yu
AU - Yan Lin
AU - Dingwen Zhang
AU - Bingxin Cao
AU - Haoming Zhong
AU - Changhao Chen
AU - Rufu Chen
PY - 2026
DA - 2026/10/01
JO - Journal of extracellular vesicles
DO - 10.1002/jev2.70383
UR - https://europepmc.org/article/PMC/PMC13653645
AB - KRASG12D/TP53R175H mutations are hallmarks of malignant tumor progression and are associated with lymph node (LN) metastasis in solid tumor. Nevertheless, the mechanisms underlying KRASG12D/TP53R175H co‐mutation‐mediated LN metastasis remain unclear. Herein, we developed KRASG12D/TP53R175H mutation‐related orthotopic xenograft models and demonstrated that KRASG12D/TP53R175H co‐mutation promotes the lymphangiogenesis and LN metastasis. FUS is identified by next generation sequencing to be upregulated in tumor tissues harbouring KRASG12D/TP53R175H co‐mutation across multi‐center cohorts, wherein KRASG12D‐mediated phosphorylation of TP53R175H promotes FUS transcriptional activation. Functionally, FUS‐mediated extracellular vesicle (EV) promotes lymphangiogenesis and LN metastasis in vitro and in vivo. Mechanistically, upon KRASG12D/TP53R175H co ‑ mutation, FUS regulated circSCARNA10 biosynthesis and promotes EVs secretion by stabilizing RAB3B mRNA, leading to VEGFR3 transcription in lymphatic endothelial cells to trigger lymphangiogenesis and LN metastasis. Blockade of FUS inhibits LN metastasis in KrasG12D/+Trp53R172H/+Pdx‐1‐Cre (KPC) mice model. Clinically, detecting circSCARNA10 in serum‐EVs exhibited higher diagnostic efficiency compared with traditional biomarkers, carcinoembryonic antigen (CEA) and carbohydrate antigen 19‐9 (CA19‐9) in distinguishing LN metastasis. Collectively, we highlight the precise mechanisms by which KRASG12D/TP53R175H co‐mutation mediates EV secretion to trigger LN metastasis, providing a potential therapeutic target for KRASG12D/TP53R175H co‐mutation ‐ driven LN metastasis.
SN - 2001-3078
ER -