Endosomal Trafficking Bypassed by the RAB5B-CD109 Interplay Promotes Axonogenesis in KRAS-Mutant Pancreatic Cancer.

Nov 04, 2024

Experts: Dingwen Zhang,Yuming Luo,Yan Lin,Zhou Fang,Hanhao Zheng,Mingjie An,Qingyu Xie,Zhuo Wu,Chao Yu,Jiabin Yang,Min Yu,Changhao Chen,Rufu Chen

Perineural invasion (PNI) represents a unique biological feature associated with poor prognosis in pancreatic ductal adenocarcinoma (PDAC), especially in the presence of KRAS mutations. Extracellular vesicle (EV)-packaged circular RNAs (circRNAs) function as essential mediators of tumor microenvironment communication, triggering PDAC cell invasion and distant metastasis. However, the regulatory mechanisms of EV-packaged circRNAs in the PNI of KRAS-mutant PDAC have not yet been elucidated. Herein, a KRAS mutation-responsive EV-packaged circRNA, circPNIT, which positively correlated with PNI in PDAC patients is identified. Functionally, KRAS PDAC-derived EV-packaged circPNIT promoted axonogenesis and PNI both in vitro and in vivo. Mechanistically, the circPNIT-mediated Rab5B-CD109 interplay bypassed traditional endosomal trafficking to anchor Rab5B to the lipid rafts of multivesicular bodies and packaged circPNIT into CD109 EVs. Subsequently, CD109 EVs delivered circPNIT to neurons by binding to TRPV1 and facilitating DSCAML1 transcription-induced axonogenesis, which in turn enhanced the PNI by activating the GFRα1/RET pathway. Importantly, circPNIT-loaded CD109 EVs are established to dramatically promote PNI in a KRAS Trp53 Pdx-1-Cre mouse model. Collectively, the findings highlight the mechanism underlying how EV-packaged circRNAs mediate the PNI of KRAS-mutant PDAC cells through the Rab5B endosomal bypass, identifying circPNIT as an effective target for the treatment of neuro-metastatic PDAC.
© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.

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ABOUT THE EXPERTS

Dingwen Zhang,Yuming Luo,Yan Lin,Zhou Fang,Hanhao Zheng,Mingjie An,Qingyu Xie,Zhuo Wu,Chao Yu,Jiabin Yang,Min Yu,Changhao Chen,Rufu Chen

Dingwen Zhang

School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, P. R. China.

Department of Pancreatic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China.

Yuming Luo

Department of Pancreatic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China.

Yan Lin

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, P. R. China.

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510120, P. R. China.

Zhou Fang

Department of Pancreatic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China.

The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510080, P. R. China.

Hanhao Zheng

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, P. R. China.

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510120, P. R. China.

Mingjie An

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, P. R. China.

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510120, P. R. China.

Qingyu Xie

Department of Pancreatic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China.

The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510080, P. R. China.

Zhuo Wu

School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510006, P. R. China.

Department of Pancreatic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China.

Chao Yu

Department of Pancreatic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China.

The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510080, P. R. China.

Jiabin Yang

Department of Pancreatic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China.

The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510080, P. R. China.

Min Yu

Department of Pancreatic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China.

Changhao Chen

Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, P. R. China.

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510120, P. R. China.

Rufu Chen

Department of Pancreatic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China.