Metastasis is the major cause of treatment failure in cancer patients and of cancer-related deaths. This editorial discusses how cancer metastasis may be better perceived and controlled. Based on big-data analyses, a collection of 150 important pro-metastatic genes was studied. Using The Cancer Genome Atlas datasets to re-analyze the effect of some previously reported metastatic genes—e.g., JAM2, PPARGC1A, SIK2, and TRAF6—on overall survival of patients with renal and liver cancers, we found that these genes are actually protective factors for patients with cancer. The role of epithelial–mesenchymal transition (EMT) in single-cell metastasis has been well-documented. However, in metastasis caused by cancer cell clusters, EMT may not be necessary. A novel role of epithelial marker E-cadherin, as a sensitizer for chemoresistant prostate cancer cells by inhibiting Notch signaling, has been found. This editorial also discusses the obstacles for developing anti-metastatic drugs, including the lack of high-throughput technologies for identifying metastasis inhibitors, less application of animal models in the pre-clinical evaluation of the leading compounds, and the need for adjustments in clinical trial design to better reflect the anti-metastatic efficacy of new drugs. We are confident that by developing more effective high-throughput technologies to identify metastasis inhibitors, we can better predict, prevent, and treat cancer metastasis.

With the rapid development of the high throughput detection techniques, tumor-related Omics data has become an important source for studying the mechanism of tumor progression including breast cancer, one of the major malignancies worldwide. A previous study has shown that the G2 and S phase-expressed-1 (GTSE1) can act as an oncogene in several human cancers. However, its functional roles in breast cancer remain elusive. In this study, we analyzed breast cancer data downloaded from The Cancer Genome Atlas (TCGA) databases and other online database including the Oncomine, bc-GenExMiner and PROGgeneV2 database to identify the molecules contributing to the progression of breast cancer. The GTSE1 expression levels were investigated using qRT-PCR, immunoblotting and IHC. The biological function of GTSE1 in the growth, migration and invasion of breast cancer was examined in MDA-MB-231, MDA-MB-468 and MCF7 cell lines. The in vitro cell proliferative, migratory and invasive abilities were evaluated by MTS, colony formation and transwell assay, respectively. The role of GTSE1 in the growth and metastasis of breast cancer were revealed by in vivo investigation using BALB/c nude mice. We showed that the expression level of GTSE1 was upregulated in breast cancer specimens and cell lines, especially in triple negative breast cancer (TNBC) and p53 mutated breast cancer cell lines. Importantly, high GTSE1 expression was positively correlated with histological grade and poor survival. We demonstrated that GTSE1 could promote breast cancer cell growth by activating the AKT pathway and enhance metastasis by regulating the Epithelial-Mesenchymal transition (EMT) pathway. Furthermore, it could cause multidrug resistance in breast cancer cells. Interestingly, we found that GTSE1 could regulate the p53 function to alter the cell cycle distribution dependent on the mutation state of p53. Our results reveal that GTSE1 played a key role in the progression of breast cancer, indicating that GTSE1 could serve as a novel biomarker to aid in the assessment of the prognosis of breast cancer.

Nasopharyngeal carcinoma (NPC) is a common malignancy in Southern China and Southeast Asia. In this study, we investigated the functional and molecular mechanisms by which CDC42-interacting protein 4 (CIP4) influences NPC. The expression levels of CIP4 were examined by Western blot, qRT-PCR or IHC. MTT assay was used to detect the proliferative rate of NPC cells. The invasive abilities were examined by matrigel and transwell assay. The metastatic abilities of NPC cells were revealed in BALB/c nude mice. We report that CIP4 is required for NPC cell motility and invasion. CIP4 promotes the activation of N-WASP that controls invadopodia formation and activates EGFR signaling, which induces downstream MMP2 (matrix metalloproteinase 2) upregulation. In addition, CIP4 could promote NPC metastasis by activating the EGFR pathway. In nude mouse models, distant metastasis was significantly inhibited in CIP4-silenced groups. High CIP4 expression is an independent adverse prognostic factor of overall survival (OS) and distant metastasis-free survival (DMFS). We identify the critical role of CIP4 in metastasis of NPC which suggest that CIP4 may be a potential therapeutic target of NPC patients.

Metastasis is the greatest contributor to cancer-related death. In the era of precision medicine, it is essential to predict and to prevent the spread of cancer cells to significantly improve patient survival. Thanks to the application of a variety of high-throughput technologies, accumulating big data enables researchers and clinicians to identify aggressive tumors as well as patients with a high risk of cancer metastasis. However, there have been few large-scale gene collection studies to enable metastasis-related analyses. In the last several years, emerging efforts have identified pro-metastatic genes in a variety of cancers, providing us the ability to generate a pro-metastatic gene cluster for big data analyses. We carefully selected 285 genes with in vivo evidence of promoting metastasis reported in the literature. These genes have been investigated in different tumor types. We used two datasets downloaded from The Cancer Genome Atlas database, specifically, datasets of clear cell renal cell carcinoma and hepatocellular carcinoma, for validation tests, and excluded any genes for which elevated expression level correlated with longer overall survival in any of the datasets. Ultimately, 150 pro-metastatic genes remained in our analyses. We believe this collection of pro-metastatic genes will be helpful for big data analyses, and eventually will accelerate anti-metastasis research and clinical intervention.

Cellular metabolic reprogramming supports tumor proliferation, invasion, and metastasis by enhancing resistance to stress and immune clearance. Understanding these metabolic changes within the tumor microenvironment is vital to developing effective therapies. We conducted single-cell RNA sequencing on 11 gastric cancer (GC) samples and eight metastatic lesions, analyzing 92,842 cells across eight cell types, including cancer cells, stromal cells, and immune cells. Our findings highlight that the mitochondrial ATP synthase subunit ATP5MC2 uniquely alters during early GC metastasis. Experiments and clinical data confirmed that ATP5MC2 upregulation facilitates cancer cell proliferation, invasion, and metastasis. Constructing a single-cell atlas revealed significant immune cell heterogeneity associated with GC metastasis and its molecular subtypes. This study underscores the role of ATP5MC2-driven metabolic changes and diverse immune landscapes in promoting GC metastasis, offering new avenues for anti-metastatic treatment development.