To explore the mechanism of coadaptation and the potential drivers of pancreatic ductal adenocarcinoma (PDAC) metastasis to the liver, we study key molecules involved in this process and their translational value. Premetastatic niche (PMN) and macrometastatic niche (MMN) formation in a mouse model is observed via CT combined with 3D organ reconstruction bioluminescence imaging, and then we screen slit guidance ligand 2 (SLIT2) and its receptor roundabout guidance receptor 1 (ROBO1) as important factors. After we confirm the expression and distribution of SLIT2 and ROBO1 in samples from PDAC patients and several mouse models, we discover that SLIT2-ROBO1-mediated coadaptation facilitated the implantation and outgrowth of PDAC disseminated tumour cells (DTCs) in the liver. We also demonstrate the dependence receptor (DR) characteristics of ROBO1 in a follow-up mechanistic study. A neutralizing antibody targeting ROBO1 significantly attenuate liver metastasis of PDAC by preventing the coadaptation effect. Thus, we demonstrate that coadaptation is supported by the DR characteristics in the PMN and MMN.

Recent observations indicate a decreased cancer risk in patients with Alzheimer’s disease (AD). AD is a severe neurodegenerative disorder characterized by progressive cognitive decline. The 8q24 region has been shown to be involved in AD aetiology. We aimed to identify and explore the potential oncogenes or antioncogenes on chromosome 8q24. We compared expression of genes on Chromosome 8q24 in 32 pairs of samples from The Cancer Genome Atlas (TCGA) database. We conducted bioinformatics analysis of the commonly used gastric cancer databases and performed clinical verification of gastric cancer samples, combined with assessment of biological function both in vitro and in vivo to determine the relationship between upregulated expression of GRINA and gastric cancer progression. We also explored the molecular mechanism of GRINA upregulation and its function in gastric cancer development and progression. The expression of GRINA in cancer tissues was significantly higher than that in normal tissues. GRINA indicated poor prognosis in gastric cancer. GRINA promoted the proliferation, migration and invasion capacity of gastric cancer cells. GRINA was transcriptionally mediated by c-Myc and promotes cell cycle transition. GRINA knockdown decreased PI3K/Akt/mTOR signaling and glycolytic metabolism in gastric cancer cells. The apoptosis rate was significantly increased in gastric cancer cell lines after knockdown of GRINA. The expression of pro-apoptotic protein Bax was significantly upregulated, whereas the anti-apoptotic protein Bcl-2 was significantly downregulated in GRINA silenced cells. Human gastric cancers have increased levels of GRINA, which promotes growth of gastric cancer and inhibits tumor cells apoptosis.

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.

Gastric cancer is one of the deadliest malignant tumours, with a high incidence in China, and is regulated by aberrantly overexpressed oncogenes. However, existing therapies are insufficient to meet patients’ needs; thus, the identification of additional therapeutic targets and exploration of the underlying mechanism are urgently needed. GPAA1 is the subunit of the GPI transamidase that transfers the GPI anchor to proteins within the ER. The functional impacts of increased expression levels of GPAA1 in human cancers are not well understood. Data mining was performed to determine the pattern of GPAA1 expression and the reason for its overexpression in tumour and adjacent normal tissues. In vitro and in vivo experiments evaluating proliferation and metastasis were performed using cells with stable deletion or overexpression of GPAA1. A tissue microarray established by the Ren Ji Hospital was utilized to analyse the expression profile of GPAA1 and its correlation with prognosis. Western blotting, an in situ proximity ligation assay, and co-immunoprecipitation (co-IP) were performed to reveal the mechanism of GPAA1 in gastric cancer. GPAA1 was a markedly upregulated oncogene in gastric cancer due to chromosomal amplification. GPAA1 overexpression was confirmed in specimens from the Ren Ji cohort and was associated with ERBB2 expression, predicting unsatisfactory patient outcomes. Aberrantly upregulated GPAA1 dramatically contributed to cancer growth and metastasis in in vitro and in vivo studies. Mechanistically, GPAA1 enhanced the levels of metastasis-associated GPI-anchored proteins to increase tumour metastasis and intensified lipid raft formation, which consequently promoted the interaction between EGFR and ERBB2 as well as downstream pro-proliferative signalling. GPAA1 facilitates the expression of cancer-related GPI-anchored proteins and supplies a more robust platform—the lipid raft—to promote EGFR-ERBB2 dimerization, which further contributes to tumour growth and metastasis and to cancer progression. GPAA1 could be a promising diagnostic biomarker and therapeutic target for gastric cancer.

Background: Drug resistance and tumor recurrence are the major concerns in clinical practices of gastrointestinal stromal tumor (GIST), with the urgent requirement for exploring undiscovered pathways driving malignancy. To deal with these, recent studies have made many efforts to explore prognosis indicators and establish potential therapeutic targets. Methods: Expression profiles of different risks of GISTs were described and abundant clinical evidences supported our findings in this study. Following exploration in vitro by cell experiments and verification in vivo using tumor microarray were taken to elucidate the underlying mechanism, which drove the malignancy in GIST. Results: Dickkopf 4 (DKK4), as the canonical Wnt pathway antagonist, was unexpectedly and universally upregulated in high‐risk GISTs, and aberrant accumulation of DKK4 was closely correlated with poor prognosis. In addition, tumor‐derived DKK4 could decrease immune cells infiltration and activation in the tumor microenvironment, which decreased the antitumor effects in return. And this phenomenon was recurrent in human tumor specimens. Conclusions: Our findings identified DKK4 as a proper tumor biomarker for prognosis predicting and recurrence monitoring, and suggested a novel immune‐escape mechanism driving malignancy in GIST, which might be a potential therapeutic target to improve the effects of canonical RTK therapy and combined immunotherapy.

Background Liver is one of the target organs bearing the most frequent distant metastasis of gastric cancer (GC), and patients with GC liver metastasis suffering from poor prognosis. According to “seed and soil” theory, important and complex interactions between disseminated tumor cells (DTCs) and metastasis tumor microenvironment (MTM) have played a vital role in waking the dormant DTCs and promoting their proliferation. We have discovered that the aberrantly activated cancer associated fibroblasts (CAFs) could significantly increase the enrichment and stiffness of extracellular matrix (ECM). ECM with high stiffness could facilitate the accumulation of Troponin T1, slow skeletal type (TNNT1) in cytoplasm for dormant DTCs awaking and proliferation. Methods We set off from observing the stiffness of ECM around liver metastatic niches of GC and performed in vivo and in vitro study for further study. Based on the gained information, we plan to further unveil the underlying mechanism and explore the clinical transformation value using the ex-vivo and patient derived xenograft (PDX) model. Conclusion Our study aims to illustrate the relationship between ECM stiffness and tumor dormancy awakening in liver metastasis of GC and provide reliable theoretical and research basis for treatment of GC liver metastasis.