Liver Metastasis Of Gastric Cancer Research Articles

The Value of Primary Tumor Resection in Patients with Liver Metastases: A 10-Year Outcome.

This study aimed to analyze the impact of primary tumor resection (PTR) on the prognosis of four common primary tumors with liver metastases, and to develop a prognostic model to visualize the PTR benefit rate of patients with liver metastases. Patients diagnosed with colorectal cancer liver metastases (CRLM), pancreatic cancer liver metastases (PLM), gastric cancer liver metastases (GLM), and breast cancer liver metastases (BLM) between 2004 and 2015 were retrospectively reviewed from the Surveillance, Epidemiology, and End Results (SEER) database and assigned to either the surgery or non-surgery groups. A 1:1 propensity score matching (PSM) was performed. Surgical patients who survived longer than the median cancer-specific survival (CSS) time for non-surgery patients constituted the benefit group. Logistic regression was conducted to explore the independent factors affecting surgical benefit, and a nomogram was established. A total of 21,928 patients with liver metastases were included. After PSM for surgery and non-surgery patients, we found that PTR had a significant impact on the overall survival (OS) and CSS of CRLM, PLM, and BLM patients. In CRLM patients, age (p<0.001), primary site (p=0.006), grade (p=0.009), N stage (p=0.034), and histology (p=0.006) affected the surgical benefit. In BLM patients, the independent factors were age (p=0.002), race (p=0.020), and radiotherapy (p=0.043). And in PLM patients, chemotherapy was an independent factor associated with a survival benefit from PTR. PTR improved OS and CSS in patients with CRLM, PLM, and BLM. A predictive model was established to identify suitable candidates for PTR in CRLM patients.

Ephrin A1 Stimulates CCL2 Secretion to Facilitate Pre-metastatic Niche Formation and Promote Gastric Cancer Liver Metastasis.

The liver is a primary target for distal metastasis of gastric cancer (GC). The hepatic pre-metastatic niche (PMN) facilitates crucial communications between primary tumor and liver, thereby playing an essential role in hepatic metastasis. Identification of the molecular mechanisms driving PMN formation in GC could facilitate development of strategies to prevent and treat liver metastasis. Here, we uncovered a role for ephrin A1 (EFNA1) signaling in development of the PMN. EFNA1 overexpression in GC cells significantly increased CCL2 secretion through the Hippo-YAP pathway. Secreted CCL2 activated hepatic stellate cells (HStCs) within the hepatic PMN via the WNT/β-catenin pathway. Inhibition of CCL2 significantly suppressed HStC activation and reduced liver metastasis triggered by EFNA1 signaling in GC cells. Moreover, high CCL2 expression correlated with poor survival in GC patients. Overall, these findings reveal that EFNA1 signaling in GC cells upregulates CCL2, which activates HStCs to engender establishment of a hepatic pre-metastatic niche that supports liver metastasis.

Circadian system disorder induced by aberrantly activated EFNB2-EPHB2 axis leads to facilitated liver metastasis in gastric cancer

Circadian system disorder induced by aberrantly activated EFNB2-EPHB2 axis leads to facilitated liver metastasis in gastric cancer

Analysis of risk factors for liver metastasis in patients with gastric cancer and construction of prediction model: A multicenter study

BackgroundTo retrospectively analyze the risk factors of liver metastases in patients with gastric cancer in a single center, and to establish a Nomogram prediction model to predict the occurrence of liver metastases.MethodsA total of 96 patients with gastric cancer who were also diagnosed with liver metastasis (GCLM) and treated in our center from January 1, 2010 to December 31, 2020 were included. The clinical data of 1095 patients with gastric cancer who were diagnosed without liver metastases (GC) in our hospital from January 1, 2014 to December 31, 2017 were retrospectively compared by univariate and multivariate logistic regression. 309 patients diagnosed with gastric cancer in another medical center from January 1, 2014 to December 31, 2018 were introduced as external validation cohorts.ResultsBased on the training cohort, multivariate analysis revealed that tumor site (OR = 0.55, P = 0.046), N stage (OR = 4.95, P = 0.004), gender (OR = 0.04, P = 0.001), OPNI (OR = 0.95, P = 0.041), CEA (OR = 1.01, P = 0.018), CA724 (OR = 1.01, P = 0.006), CA242 (OR = 1.01, P = 0.006), WBC (OR = 1.13, P = 0.024), Hb (OR = 0.98, P < 0.001) were independent risk factors for liver metastasis in patients with gastric cancer, and Nomogram was established based on this analysis (C-statistics = 0.911, 95%CI 0.880–0.958), and the C-statistics of the external validation cohorts achieved 0.926. ROC analysis and decision curve analysis (DCA) revealed that the nomogram provided superior diagnostic value than single variety.ConclusionsBy innovatively introducing a new tumor location classification method, systemic inflammatory response indicators such as NLR and PLR, and nutritional index OPNI, the risk factors of gastric cancer liver metastasis were determined and a predictive Nomogram model was established, which can provide clinical prediction for patients with gastric cancer liver metastasis.

Single-cell profiling reveals altered immune landscape and impaired NK cell function in gastric cancer liver metastasis.

Gastric cancer (GC) is a substantial global health concern, and the development of liver metastasis (LM) in GC represents a critical stage linked to unfavorable patient prognoses. In this study, we employed single-cell RNA sequencing (scRNA-seq) to investigate the immune landscape of GC liver metastasis, revealing several immuno-suppressive components within the tumor immune microenvironment (TIM). Our findings unveiled an increased presence of cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cell (MDSC)-like macrophages, tumor-associated macrophage (TAM)-like macrophages, and naive T cells, while conventional dendritic cells (cDCs) and effector CD8 T cells declined in LM. Additionally, we identified two distinct natural killer (NK) cell clusters exhibiting differential cytotoxicity-related gene expression, with cytotoxic NK cells notably reduced in LM. Strikingly, TGFβ was identified as an inducer of NK cell dysfunction, potentially contributing to immune evasion and tumor metastasis. In preclinical LM models, the combined approach of inhibiting TGFβ and transferring NK cells exhibited a synergistic impact, resulting in a significant reduction in liver metastasis. This work highlights the importance of understanding the complex immune dynamics within GC liver metastasis and presents a promising strategy combining TGFβ inhibition and NK-based immunotherapy to improve patient outcomes.

Distinct characteristics of distant metastasis in early-onset gastric cancer patients compared to late-onset patients: An observational study.

Presently, there is limited understanding of the features of distant metastasis in early-onset gastric cancer (GC). To explore these disparities, a retrospective study utilizing the Surveillance, Epidemiology, and End Results (SEER) database was undertaken. The SEER database was utilized to extract patient data, and multivariate logistic regression analysis was employed to identify the risk factors associated with distant metastasis and liver metastasis. Propensity score matching (PSM) was used to compare the occurrence of liver metastasis among patients based on their age at diagnosis. The study included 2684 early-onset GC patients and 33,289 late-onset GC patients. Preliminary data analysis indicated that early-onset GC patients exhibited more aggressive characteristics such as poor cell differentiation, advanced T stage, and a higher incidence of distant metastasis, excluding liver metastasis. Multivariate logistic regression analysis identified younger age as an independent risk factor for distant metastasis, along with T stage, lymph node metastasis (LNM), and tumor size (>3 cm). Another regression analysis revealed that younger age, diffuse type, and female gender were protective factors against liver metastasis. Through PSM, 3276 early-onset GC patients were matched with an equal number of late-onset GC patients, revealing that patients with early-onset GC had fewer instances of liver metastasis but a higher prevalence of distant metastasis. Our findings suggest that early-onset serves as a protective factor against liver metastasis in GC, while it poses a risk for distant metastasis, likely influenced by the increased prevalence of diffuse-type GC in early-onset patients.

Combination of clinical and spectral-CT iodine concentration for predicting liver metastasis in gastric cancer: a preliminary study.

This study aimed to determine the diagnostic efficacy of various indicators and models for the prediction of gastric cancer with liver metastasis. Clinical and spectral computed tomography (CT) data from 80 patients with gastric adenocarcinoma who underwent surgical resection were retrospectively analyzed. Patients were divided into metastatic and non-metastatic groups based on whether or not to occur liver metastasis, and the region of interest (ROI) was measured manually on each phase iodine map at the largest level of the tumor. Iodine concentration (IC), normalized iodine concentration (nIC), and clinical data of the primary gastric lesions were analyzed. Logistic regression analysis was used to construct the clinical indicator (CI) and clinical indicator-spectral CT iodine concentration (CI-Spectral CT-IC) Models, which contained all of the parameters with statistically significant differences between the groups. Receiver operating characteristic (ROC) curves were constructed to evaluate the accuracy of the models. The metastatic group showed significantly higher levels of Cancer antigen125 (CA125), carcinoembryonic antigen (CEA), IC, and nIC in the arterial phase, venous phase, and delayed phase than the non-metastatic group (all p < 0.05). Normalized iodine concentration Venous Phase (nICVP) exhibited a favorable performance among all IC and nIC parameters for forecasting gastric cancer with liver metastasis (area under the curve (AUC), 0.846). The combination model of clinical data with significant differences and nICVP showed the best diagnostic accuracy for predicting liver metastasis from gastric cancer, with an AUC of 0.897. nICVP showed the best diagnostic efficacy for predicting gastric cancer with liver metastasis. Clinical Indicators-normalized ICVP model can improve the prediction accuracy for this condition.

Progress and implementing of novel surgical concepts and techniques in patients with resectable gastric cancer liver metastasis

In recent years, advances in surgical techniques and evolving concepts have significantly improved treatment strategies and prognosis for patients with gastric cancer liver metastases. In particular, patients diagnosed with initially resectable gastric cancer liver metastases shows marked improvement in survival. Despite variations in the definition of initially resectable gastric cancer liver metastases among different consensus and guidelines, surgical resection and hepatic physiotherapy are increasingly crucial components of comprehensive treatment. Meanwhile, the advancement of the multidisciplinary team model for diagnosis and treatment, along with the evolution of minimally invasive surgical concepts, offers patients increasingly personalized and less intrusive therapeutic alternatives. According to the Chinese Consensus Classification System for Gastric Cancer Liver Metastasis, the optimal clinical pathway for patients initially diagnosed with resectable gastric cancer liver metastasis involves precise categorization, guided selection of surgical approaches and physiotherapy using the multidisciplinary team model, and consideration of molecular classification. However, the refinement and confirmation of these clinical strategies is still required through high-quality clinical trials.

MEF2D facilitates liver metastasis of gastric cancer cells through directly inducing H1X under IL-13 stimulation

Liver metastasis is the most common metastatic occurrence in gastric cancer patients, although the precise mechanism behind it remains unclear. Through a combination of proteomics and quantitative RT-PCR, our study has revealed a significant correlation between the upregulation of myocyte enhancer factor-2D (MEF2D) and both distant metastasis and poor prognosis in gastric cancer patients. In mouse models, we observed that overexpressing or knocking down MEF2D in gastric cancer cells respectively promoted or inhibited liver metastasis. Furthermore, our research has demonstrated that MEF2D regulates the transcriptional activation of H1X by binding to the H1X promoter. This regulation leads to the upregulation of H1X, which, in turn, promotes the in vivo metastasis of gastric cancer cells along with the upregulation of the downstream gene β-CATENIN. Additionally, we found that the expression of MEF2D and H1X at both mRNA and protein levels can be induced by the inflammatory factor IL-13, and this induction exhibits a time gradient dependence. In human gastric cancer tissues, the expression of IL13RA1, the receptor for IL-13, positively correlates with the expression of MEF2D and H1X. IL13RA1 has been identified as an intermediate receptor through which IL-13 regulates MEF2D. In conclusion, our findings suggest that MEF2D plays a crucial role in promoting liver metastasis of gastric cancer by upregulating H1X and downstream target β-CATENIN in response to IL-13 stimulation. Targeting MEF2D could therefore be a promising therapeutic strategy for the clinical management of gastric cancer. Statement of significanceMEF2D promotes its transcriptional activation in gastric cancer cells by binding to the H1X promoter and is upregulated by IL-13-IL13RA1, thereby promoting distant metastasis of gastric cancer.

A bibliometric analysis of gastric cancer liver metastases: advances in mechanisms of occurrence and treatment options.

Gastric cancer (GC) is the fifth most commonly diagnosed cancer worldwide, and its poor prognosis is predominantly attributed to distant metastasis. The liver is the primary site of GC metastasis. However, there is no universally approved treatment regimen for liver metastasis in GC. The aim of this article is to review the current research status and trends of liver metastasis of GC worldwide. The authors utilized the Web of Science Core Collection database to identify articles on liver metastasis from GC published between 2000 and 2022. The authors used bibliometric methods to analyze authors, institutions, countries, journals, and references through CiteSpace and VOSviewer. A total of 1003 articles were included in this study. Japan published the most articles in the field, followed by China. Nagoya University is the leading institution in the field of liver metastases in GC. Yasuhiro Kodera from Japan has made significant achievements in this area. The authors identified GC to be the most influential journal in this field. Using cluster analysis, the keywords were divided into four major clusters:(1) the molecular mechanism of GC liver metastasis, (2) prognosis, (3) liver resection, and (4) chemotherapy. Our study systematically summarizes the results of GC liver metastasis research from 2000 to 2022 and describes and predicts research hotspots and trends on a global scale. Research on the molecular mechanisms of GC liver metastasis will become a hot topic in the future, and the expansion of the surgical treatment scope and the advancement of translational therapy will benefit more patients.

Abstract 1489: The role of EPAS1 and TEAD1 in gastric cancer liver metastasis

Abstract Gastric cancer ranks fifth in incidence and fourth for cancer-related mortality worldwide. While the liver is widely recognized as the leading site of metastasis in gastric cancer, the intricate mechanisms underpinning its tropism toward the liver and the hematogenous metastasis process remain poorly understood and demand further investigation. Hematogenous metastasis encompasses the generation of circulating tumor cells from the primary tumor site and their subsequent attachment to the metastatic niche. This process involves the transition between adherent and suspension states. In our investigation of anchorage dependency, we identified 20 transcription factors upregulated in suspension cells compared to adherent cells and 18 transcription factors upregulated in adherent cells relative to suspension cells, respectively. To investigate factors involved in gastric cancer metastasis, RNA sequencing of paired primary and metastatic tissue samples obtained from 15 patients diagnosed with advanced gastric cancer was conducted, which disclosed the selective upregulation of EPAS1 and TEAD1 in metastatic liver tissue compared to the matched primary tumor tissue and the metastatic tissue originating from other sites. Through in vitro analysis, we observed a portion of adherent cells transitioning into suspension cells when subjected to a hyperdense environment. We also observed cell reattachment upon harvesting and replating these suspension-state transited cells. Comparing EPAS1 and TEAD1 expression in these states unveiled increased expression of EPAS1 and TEAD1 in reattached cells relative to suspension-state cells. We established a gastric cancer metastasis mouse model introducing gastric cancer cells into the mouse circulatory system via intracardiac injection to validate our findings. In vivo imaging was utilized to confirm systemic metastasis. After fluorescence-based cell sorting, EPAS1 and TEAD1 expression in cancer cells collected from the blood, liver, and ovary were assessed. We detected higher expression of EPAS1 and TEAD1 in liver metastasis compared to the circulating tumor cells. Furthermore, EPAS1 and TEAD1 were upregulated in liver metastatic cancer cells compared to ovarian metastatic cancer cells. Our findings underscore EPAS1 and TEAD1 as pivotal factors governing gastric cancer liver tropism and metastasis, offering insights that may contribute to targeted interventions in the clinical landscape. Citation Format: DONG KI Lee, Hyun Woo Park, Jae-Ho Cheong, Heon Yung Gee. The role of EPAS1 and TEAD1 in gastric cancer liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1489.

High serum alpha-fetoprotein and positive immunohistochemistry of alpha-fetoprotein are related to poor prognosis of gastric cancer with liver metastasis

Liver metastasis in gastric cancer is incurable. Alpha-fetoprotein-producing gastric cancer has a poor prognosis and is prone to liver metastasis. We investigated the association between preoperative serum alpha-fetoprotein levels, liver metastasis, and expression of primitive enterocyte phenotype markers. We reviewed the medical records of 401 patients with gastric cancer who underwent curative surgical resection and immunohistochemically evaluated the primitive phenotype markers. The preoperative serum alpha-fetoprotein levels were elevated and normal in 8 and 393 patients, respectively. Liver metastasis was more frequent in patients with higher preoperative alpha-fetoprotein levels. The 5-year postoperative recurrence-free survival and overall survival rates were significantly worse in patients with higher preoperative serum alpha-fetoprotein levels. Although alpha-fetoprotein and Glypican3 and Spalt-like transcription factor 4 tended to be stained with high preoperative serum alpha-fetoprotein levels, these markers were also positive in some patients with normal alpha-fetoprotein levels. In summary, patients with gastric cancer and high preoperative serum alpha-fetoprotein levels have a poor prognosis and high incidence of liver metastasis. Alpha-fetoprotein can help detect liver metastasis relating to the primitive enterocyte phenotype.

Resection of liver metastasis of gastric cancer: literature review and case report

Resection of liver metastasis of gastric cancer: literature review and case report

Development and validation of nomogram models for predicting overall survival and cancer-specific survival in gastric cancer patients with liver metastases: a cohort study based on the SEER database.

To establish nomogram models for predicting the overall survival (OS) and cancer-specific survival (CSS) of gastric cancer liver metastasis (GCLM) patients. Data from the Surveillance, Epidemiology, and End Results (SEER) database for 5,451 GCLM patients diagnosed between 2010 and 2015 were analyzed. The cohort was divided into a training set (3,815 cases) and an internal validation set (1,636 cases). External validation included 193 patients from the Fourth Hospital of Hebei Medical University and 171 patients from the People's Hospital of Shijiazhuang City, spanning 2016-2018. Multivariable Cox regression analysis identified eight independent prognostic factors for OS and CSS in GCLM patients, including age, histological type, grade, tumor size, surgery, chemotherapy, bone metastasis, and lung metastasis. Two nomogram models were developed based on these factors and evaluated using time-dependent receiver operating characteristic curve analysis, calibration curves, and decision curve analysis. Internal validation showed that the nomogram models outperformed the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system in predicting 1-year, 2-year, and 3-year OS and CSS in GCLM patients (1-year OS: 0.801 vs. 0.593, P < 0.001; 1-year CSS: 0.807 vs. 0.598, P < 0.001; 2-year OS: 0.803 vs. 0.630, P < 0.001; 2-year CSS: 0.802 vs. 0.633, P < 0.001; 3-year OS: 0.824 vs. 0.691, P < 0.001; 3-year CSS: 0.839 vs. 0.692, P < 0.001). This study developed and validated nomogram models using SEER database data to predict OS and CSS in GCLM patients. These models offer improved prognostic accuracy over traditional staging systems, aiding in clinical decision-making.

Trends in long-term survival after liver resection for gastric cancer liver metastasis: Analysis of a single center experience over 28 years

Trends in long-term survival after liver resection for gastric cancer liver metastasis: Analysis of a single center experience over 28 years

Clinical landscape and prognosis of patients with gastric cancer liver metastases: A nation-wide multicenter cohort study in China (RECORD study)

Clinical landscape and prognosis of patients with gastric cancer liver metastases: A nation-wide multicenter cohort study in China (RECORD study)

The regulatory role of cancer stem cell marker gene CXCR4 in the growth and metastasis of gastric cancer

Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq) are increasingly used for screening genes involved in carcinogenesis due to their capacity for dissecting cellular heterogeneity. This study aims to reveal the molecular mechanism of the cancer stem cells (CSCs) marker gene CXCR4 in gastric cancer (GC) growth and metastasis through scRNA-seq combined with bulk RNA-seq. GC-related scRNA-seq data were downloaded from the GEO database, followed by UMAP cluster analysis. Non-malignant cells were excluded by the K-means algorithm. Bulk RNA-seq data and clinical sample information were downloaded from the UCSC Xena database. GO and KEGG pathway analyses validated the correlation between genes and pathways. In vitro and in vivo functional assays were used to examine the effect of perturbed CXCR4 on malignant phenotypes, tumorigenesis, and liver metastasis. A large number of highly variable genes were identified in GC tissue samples. The top 20 principal components were selected, and the cells were clustered into 6 cell types. The C4 cell cluster from malignant epithelial cells might be CSCs. CXCR4 was singled out as a marker gene of CSCs. GC patients with high CXCR4 expression had poor survival. Knockdown of CXCR4 inhibited the malignant phenotypes of CSCs in vitro and curtailed tumorigenesis and liver metastasis in nude mice. CSC marker gene CXCR4 may be a key gene facilitating malignant phenotypes of CSCs, which thus promotes tumor growth and liver metastasis of GC.

Efficacy and safety of CalliSpheres® microspheres drug-eluting beads transarterial chemoembolization in GCLM combined trans-arterial infusion therapy for treating primary focus of gastric cancer: a multi-center retrospective study

ABSTRACT Background The purpose of this study was to observe the safety and efficacy of CalliSpheres microspheres drug-eluting beads (DEB) transhepatic arterial chemoembolization (CSM-TACE) for liver metastasis of gastric cancer (GCLM) combined with trans-arterial infusion therapy (TAIT) as the primary focus of gastric cancer. Research design and methods Unresectable advanced GCLM patients were collected for retrospective analysis. Patients who progressed after chemotherapy or could not receive systematic chemotherapy were selected. CSM-TACE was used for GCLM treatment and oxaliplatin for TAIT of primary focus of gastric cancer. Adverse reactions, tumor reactions, survival rate, and survival time during treatment were recorded, and prognostic factors were analyzed. Results Forty-three patients from four oncology centers met inclusion criteria and were enrolled. CSM-TACE averaged (1.51 ± 0.51) times and TAIT averaged (4.58 ± 1.65) times. The follow-up time was 2.5–49 months, and the 6-month, 1-year, and 2-year survival rates were 86.0%, 72.1%, and 41.9%, respectively, with a median overall survival of 11.5 months. The adverse reactions during treatment were grade 1–3. The hazard ratio (HR) of combination therapy was 0.51 (P = 0.040), and the HR of TAIT frequency was 0.34 (P = 0.002), which were independent protective factors affecting prognosis. Conclusions CSM-TAC for GCLM combined with TAIT for primary focus of gastric cancer is safe and efficacious, which is worthy of clinical promotion and application.

The SLITRK4-CNPY3 axis promotes liver metastasis of gastric cancer by enhancing the endocytosis and recycling of TrkB in tumour cells.

Gastric cancer (GC) is a malignant tumour with high mortality, and liver metastasis is one of the main causes of poor prognosis. SLIT- and NTRK-like family member 4 (SLITRK4) plays an important role in the nervous system, such as synapse formation. Our study aimed to explore the functional role of SLITRK4 in GC and liver metastasis. The mRNA level of SLITRK4 was evaluated using publicly available transcriptome GEO datasets and Renji cohort. The protein level of SLITRK4 in the tissue microarray of GC was observed using immunohistochemistry. Cell Counting Kit-8, colony formation, transwell migration assays in vitro and mouse model of liver metastasis in vivo was performed to investigate the functional roles of SLITRK4 in GC. Bioinformatics predictions and Co-IP experiments were applied to screen and identify SLITRK4-binding proteins. Western blot was performed to detect Tyrosine Kinase receptor B (TrkB)-related signaling molecules. By comparing primary and liver metastases from GC, SLITRK4 was found to be upregulated in tissues of GC with liver metastasis and to be closely related topoor clinical prognosis. SLITRK4 knockdown significantly abrogated the growth, invasion, and metastasis of GC in vitro and in vivo. Further study revealed that SLITRK4 could interact with Canopy FGF Signalling Regulator 3 (CNPY3), thus enhancing TrkB- related signaling by promoting the endocytosis and recycling of the TrkB receptor. In conclusion, the CNPY3-SLITRK4 axis contributes to liver metastasis of GC according to the TrkB-related signaling pathway. which may be a therapeutic target for the treatment of GC with liver metastasis.

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

PurposeLiver 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.MethodsA 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.ResultsIn 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.ConclusionFrom 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.