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

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.

Analysis of the impact of immunotherapy efficacy and safety in patients with gastric cancer and liver metastasis

“…The outlook for patients with GC who have distant organ metastases is typically unfavorable[ 15 ]. The liver is the primary organ that GC spreads to, with a liver metastasis rate ranging from 36% to 40%[ 16 - 20 ]. Immune checkpoint inhibitors have emerged as a novel therapeutic choice for individuals with advanced malignancies.…”

Tumour‐associated macrophages in gastric cancer: From function and mechanism to application

“…Furthermore, EVs containing ApoE derived from M2 TAMs activated the PI3K–Akt pathway to enhance the cell migration of GC cells 38 . Several studies have reported and validated the promoting effects of M2 TAMs on cell migration and invasion in GC 14,60,61,85,88,109,113–116 …”

The regulatory role of autophagy between TAMs and tumor cells

“…63 Accumulating evidence shows that TAMs could induce cytoprotective autophagy in some tumor cells. [64][65][66] Autophagy and infiltration of M2-like TAMs are mutually regulated. Therefore, the inhibition of TAM-induced autophagy in hepatocellular carcinoma enhances the cytotoxicity of the chemotherapeutic agent oxaliplatin against hepatocellular carcinoma cells.…”

“…Accumulating evidence shows that TAMs could induce cytoprotective autophagy in some tumor cells 64–66 . Autophagy and infiltration of M2‐like TAMs are mutually regulated.…”

“…M2 macrophages secrete IL‐17(interleukin‐17) to stimulate chaperon‐mediated autophagy in tumor cells to help them avoid apoptosis 58 . glial cell line‐derived neurotrophic factor (GDNF), secreted by TAMs, can regulate lysosomal function through the GDNF‐ anti‐GDNF family receptor alpha 1 (GFRA1) axis to enhance autophagy flux in gastric cancer cells, resulting tumor cells survive and colonize in the metastatic microenvironment of the liver 66 . TAMs‐exosome H19 significantly promote autophagy status of bladder cancer cells by stabilizing the expression of UNC‐51‐like kinase 1 (ULK1), and thus as a potential target for the treatment of bladder cancer 88 .…”