2. Academic Validation
  3. Tumor-associated macrophage-derived GDNF promotes gastric cancer liver metastasis via a GFRA1-modulated autophagy flux

Tumor-associated macrophage-derived GDNF promotes gastric cancer liver metastasis via a GFRA1-modulated autophagy flux

  • Cell Oncol (Dordr). 2023 Feb 20. doi: 10.1007/s13402-022-00751-z.
Bo Ni 1 2,  Xuan He 3,  Yeqian Zhang 1,  Zeyu Wang 1,  Zhongyi Dong 1,  Xiang Xia 1,  Gang Zhao 1,  Hui Cao 1,  Chunchao Zhu 1,  Qing Li 4,  Jiahua Liu 5,  Huimin Chen 6,  Zizhen Zhang 7
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Road, Shanghai, China.
  • 2 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 13851601478@163.com.
  • 5 Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Road, Shanghai, China. maxlau_9@126.com.
  • 6 State Key Laboratory for Oncogenes and Related GenesKey Laboratory of Gastroenterology & Hepatology, Ministry of HealthDivision of Gastroenterology and HepatologyShanghai Institute of Digestive DiseaseRenji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. chenhuimin@renji.com.
  • 7 Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Road, Shanghai, China. zzzhang16@hotmail.com.
PMID: 36808605 DOI: 10.1007/s13402-022-00751-z
Abstract

Purpose: Liver metastasis, a lethal malignancy of gastric Cancer (GC) patients, execrably impairs their prognosis. As yet, however, few studies have been designed to identify the driving molecules during its formation, except screening evidence pausing before their functions or mechanisms. Here, we aimed to survey a key driving event within the invasive margin of liver metastases.

Methods: A metastatic GC tissue microarray was used for exploring malignant events during liver-metastasis formation, followed by assessing the expression patterns of glial cell-derived neurotrophic factor (GDNF) and GDNF family receptor alpha 1 (GFRA1). Their oncogenic functions were determined by both loss- and gain-of-function studies in vitro and in vivo, and validated by rescue experiments. Multiple cell biological studies were performed to identify the underlying mechanisms.

Results: In the invasive margin, GFRA1 was identified as a pivotal molecule involved in cellular survival during liver metastasis formation, and we found that its oncogenic role depends on tumor associated macrophage (TAM)-derived GDNF. In addition, we found that the GDNF-GFRA1 axis protects tumor cells from Apoptosis under metabolic stress via regulating lysosomal functions and Autophagy flux, and participates in the regulation of cytosolic calcium ion signalling in a RET-independent and non-canonical way.

Conclusion: From our data we conclude that TAMs, homing around metastatic nests, induce the Autophagy flux of GC cells and promote the development of liver metastasis via GDNF-GFRA1 signalling. This is expected to improve the comprehension of metastatic pathogenesis and to provide a novel direction of research and translational strategies for the treatment of metastatic GC patients.

Keywords

Autophagy; GFRA1.; Gastric cancer; Liver metastasis; Tumor associated macrophage.

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