Nasopharyngeal carcinoma (NPC) is prevalent in Asia and exhibits highly metastatic characteristics, leading to uncontrolled disease progression. Isoliquiritigenin (ISL) have attracted attention due to their diverse biological and pharmacological properties, including anticancer activities. However, the impact of ISL on the invasive and migratory ability of NPC remains poorly understood. Hence, this study aimed to investigate the in vitro anti-metastatic effects of ISL on NPC cells and elucidate the underlying signalling pathways. Human NPC cell NPC-39 and NPC-BM were utilized as cell models. Migratory and invasive capabilities were evaluated through wound healing and invasion assays, respectively. Gelatin zymography was employed to demonstrate matrix metalloproteinase-2 (MMP-2) activity, while western blotting was conducted to analyse protein expression levels and explore signalling cascades. Overexpression of signal transducer and activator of transcription 3 (STAT3) was carried out by transduction of STAT3-expressing vector. Our findings revealed that ISL effectively suppressed the migration and invasion of NPC cells. Gelatin zymography and Western blotting assays demonstrated that ISL treatment led to a reduction in MMP-2 enzyme activity and protein expression. Investigation of signalling cascades revealed that ISL treatment resulted in the inhibition of STAT3 phosphorylation. Moreover, overexpression of STAT3 restored the migratory ability of NPC cells in the presence of ISL. Collectively, these findings indicate that ISL inhibits the migration and invasion of NPC cells associating with MMP-2 downregulation through suppressing STAT3 activation. This suggests that ISL has an anti-metastatic effect on NPC cells and has potential therapeutic benefit for NPC treatment.

Cancer metastasis and therapy resistance are intricately linked with the dynamics of Epithelial-Mesenchymal Transition (EMT) and Circulating Tumor Cells (CTCs). EMT hybrid cells, characterized by a blend of epithelial and mesenchymal traits, have emerged as pivotal in metastasis and demonstrate remarkable plasticity, enabling transitions across cellular states crucial for intravasation, survival in circulation, and extravasation at distal sites. Concurrently, CTCs, which are detached from primary tumors and travel through the bloodstream, are crucial as potential biomarkers for cancer prognosis and therapeutic response. There is a significant interplay between EMT hybrid cells and CTCs, revealing a complex, bidirectional relationship that significantly influences metastatic progression and has a critical role in cancer drug resistance. This resistance is further influenced by the tumor microenvironment, with factors such as tumor-associated macrophages, cancer-associated fibroblasts, and hypoxic conditions driving EMT and contributing to therapeutic resistance. It is important to understand the molecular mechanisms of EMT, characteristics of EMT hybrid cells and CTCs, and their roles in both metastasis and drug resistance. This comprehensive understanding sheds light on the complexities of cancer metastasis and opens avenues for novel diagnostic approaches and targeted therapies and has significant advancements in combating cancer metastasis and overcoming drug resistance.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, often diagnosed at the advanced stage (metastatic). Treatment options for metastatic NSCLC include radiotherapy, chemotherapy, target drug therapy, and immunotherapy. Immunotherapy (utilization of checkpoint inhibitors) boosts the immune system to recognize and destroy cancer cells. However, it is often associated with immune-related complications such as pneumonitis. This review aims to determine the incidence of pneumonitis in metastatic NSCLC patients treated with different immunotherapy drugs. PubMed, Cochrane Library, and Embase databases were scoured for randomized controlled trials (RCTs) until October 2023. Published RCTs with similar research objectives were included, while non-English articles, reviews, case reports, ongoing trials, non-randomized studies, conference abstracts, and studies on small cell lung cancer (SCLC) were excluded. The Cochrane risk-of-bias tool for randomized trials (RoB 2) was used to assess the risk of bias among the included studies. The statistical analyses were performed with the Comprehensive Meta-Analysis software. The subgroup analysis of the 16 included RCTs showed that metastatic NSCLC patients treated with nivolumab and pembrolizumab had a higher incidence of any grade pneumonitis than those treated with atezolizumab (4.5% and 5.1% vs. 1.6%, respectively). Similarly, the incidence of grade ≥3 pneumonitis was higher among patients receiving nivolumab (1.3%) and pembrolizumab (2.4%) than those receiving atezolizumab (0.7%). Furthermore, the subgroup analysis showed that patients with naive-treated NSCLC on immunotherapy had a higher incidence of any grade pneumonitis than those with previously treated NSCLC (6.5% vs. 3.9%). Treatment-naive patients recorded higher grade ≥3 pneumonitis incidences than those previously treated (3.1% vs. 1.3%). Programmed death 1 (PD-1) inhibitors (i.e., pembrolizumab and nivolumab) have higher incidences of pneumonitis than programmed death-ligand 1 inhibitors (atezolizumab).

Tumor-derived exosomes bind to organ resident cells, activating S100 molecules during the remodeling of the local immune microenvironment. However, little is known regarding how organ resident cell S100A10 mediates cancer metastatic progression. Here, we provided evidence that S100A10 plays an important role in regulating the lung immune microenvironment and cancer metastasis. S100A10-deficient mice reduced cancer metastasis in the lung. Furthermore, the activation of S100A10 within lung fibroblasts via tumor-derived exosomes increased the expression of CXCL1 and CXCL8 chemokines, accompanied by the myeloid-derived suppressor cells (MDSCs) recruitment. S100A10 inhibitors such as 1-Substituted-4-Aroyl-3-hydroxy-5-Phenyl-1 H-5-pyrrol-2(5 H)-ones inhibit lung metastasis in vivo. Our findings highlight the crucial role of S100A10 in driving MDSC recruitment in order to remodel the lung immune microenvironment and provide potential therapeutic targets to block cancer metastasis to the lung.

Studies have identified genes and molecular pathways regulating cancer metastasis. However, it remains largely unknown whether metastatic potentials of cancer cells from different lineage types are driven by the same or different gene networks. Here, we aim to address this question through integrative analyses of 493 human cancer cells\' transcriptomic profiles and their metastatic potentials in vivo. Using an unsupervised approach and considering both gene coexpression and protein-protein interaction networks, we identify different gene networks associated with various biological pathways (i.e. inflammation, cell cycle, and RNA translation), the expression of which are correlated with metastatic potentials across subsets of lineage types. By developing a regularized random forest regression model, we show that the combination of the gene module features expressed in the native cancer cells can predict their metastatic potentials with an overall Pearson correlation coefficient of 0.90. By analyzing transcriptomic profile data from cancer patients, we show that these networks are conserved in vivo and contribute to cancer aggressiveness. The intrinsic expression levels of these networks are correlated with drug sensitivity. Altogether, our study provides novel comparative insights into cancer cells\' intrinsic gene networks mediating metastatic potentials across different lineage types, and our results can potentially be useful for designing personalized treatments for metastatic cancers.

Thyroid cancer has emerged as the most rapidly proliferating solid neoplasm. In this study, we included a cohort of patients who underwent sonographic assessment and surgical intervention at the Sir Run Run Shaw Hospital, associated with the School of Medicine at Zhejiang University, spanning from January 2019 to June 2020. Stratification of cases was based on a combination of preoperative ultrasonographic evaluations and postoperative histopathological diagnoses, resulting in three distinct groups: high-risk papillary thyroid carcinoma (PTC) labeled as C1, low-risk PTC designated as C2, and a control group (N) composed of benign thyroid tissue adjacent to the carcinoma. Proteomic and phosphoproteomic analyses were conducted on PTC specimens. The comparative assessment revealed that proteins up-regulated in the C1/N and C2/N groups were predominantly involved in functions such as amino acid binding, binding of phosphorylated compounds, and serine protease activity. Notably, proteins like NADH dehydrogenase, ATP synthase, oxidoreductases, and iron ion channels were significantly elevated in the C1 versus C2 comparative group. Through meticulous analysis of differential expression multiples, statistical significance, and involvement in metabolic pathways, this study identified eight potential biomarkers pertinent to PTC metastasis diagnostics, encompassing phosphorylated myosin 10, phosphorylated proline-directed protein kinase, leucine tRNA synthetase, 2-oxo-isovalerate dehydrogenase, succinic semialdehyde dehydrogenase, ADP/ATPtranslocase, pyruvate carboxylase, and fibrinogen. Therapeutic assays employing metformin, an AMP-activated protein kinase (AMPK) activator, alongside the phosphorylation-specific inhibitor ML-7 targeting Myosin10, demonstrated attenuated cellular proliferation, migration, and invasion capabilities in thyroid cancer cells, accompanied by a reduction in amino acid pools. Cellular colocalization and interaction studies elucidated that AMPK activation imposes an inhibitory influence on Myosin10 levels. The findings of this research corroborate the utility of proteomic and phosphoproteomic platforms in the identification of metastatic markers for PTC and suggest that modulation of AMPK activity, coupled with the inhibition of Myosin10 phosphorylation, may forge novel therapeutic avenues in the management of thyroid carcinoma. SIGNIFICANCE: The significance of our research lies in its potential to transform the current understanding and management of thyroid papillary carcinoma (PTC), particularly in its metastatic form. By integrating both proteomic and phosphoproteomic analyses, our study not only sheds light on the molecular alterations associated with PTC but also identifies eight novel biomarkers that could serve as indicators of metastatic potential.

The circulation of tumor cells through the bloodstream is a significant step in tumor metastasis. To better understand the metastatic process, circulating tumor cell (CTC) survival in the circulation must be explored. While immune interactions with CTCs in recent decades have been examined, research has yet to sufficiently explain some CTC behaviors in blood flow. Studies related to CTC mechanical responses in the bloodstream have recently been conducted to further study conditions under which CTCs might die. While experimental methods can assess the mechanical properties and death of CTCs, increasingly sophisticated computational models are being built to simulate the blood flow and CTC mechanical deformation under fluid shear stresses (FSS) in the bloodstream.Several factors contribute to the mechanical deformation and death of CTCs as they circulate. While FSS can damage CTC structure, diverse interactions between CTCs and blood components may either promote or hinder the next metastatic step-extravasation at a remote site. Overall understanding of how these factors influence the deformation and death of CTCs could serve as a basis for future experiments and simulations, enabling researchers to predict CTC death more accurately. Ultimately, these efforts can lead to improved metastasis-specific therapeutics and diagnostics specific in the future.

Over the past 20 years, increasing evidence has demonstrated that immunoglobulins (Igs) can be widely generated from non B cells, including normal and malignant mammary epithelial cells. In normal breast tissue, the expression of IgG and IgA has been identified in epithelial cells of mammary glands during pregnancy and lactation, which can be secreted into milk, and might participate in neonatal immunity. On the other hand, non B-IgG is highly expressed in breast cancer cells, correlating with the poor prognosis of patients with breast cancer. Importantly, a specific group of IgG, bearing a unique N-linked glycan on the Asn162 site and aberrant sialylation modification at the end of the novel glycan (referred to as sialylated IgG (SIA-IgG)), has been found in breast cancer stem/progenitor-like cells. SIA-IgG can significantly promote the capacity of migration, invasiveness, and metastasis, as well as enhance self-renewal and tumorigenicity in vitro and in vivo. These findings suggest that breast epithelial cells can produce Igs with different biological activities under physiological and pathological conditions. During lactation, these Igs could be the main source of milk Igs to protect newborns from pathogenic infections, while under pathological conditions, they display oncogenic activity and promote the occurrence and progression of breast cancer.

In cancer metastasis, where mortality rates remain high despite advancements in medical treatments, understanding the molecular pathways and cellular dynamics underlying tumor spread is critical for devising more effective therapeutic strategies. Here, a folding paper system was proposed and developed to mimic native tumor microenvironment. This system, composed of 7 stacked layers of paper enclosed in a holder, allows for the culture of cancer cells under conditions mimicking those found in solid tumors, including limited oxygen and nutrients. Because of the migratory capabilities of cancer cells, the cells in the center layer could migrated to outer layers of the paper stack, enabling the differentiation of cells based on their migratory potential. Subsequent gene expression analysis, conducted through RT-PCR and RNA sequencing, revealed significant correlations between cancer cell migration distance and the expression of genes associated with hypoxia, metabolism, ATP production, and cellular process. Moreover, our study identified cells with aggressive phenotypic traits from the outer layers of the paper stack, highlighting the potential of this system for enabling the study of aggressive cancer cell characteristics. Validation of the folding paper system against clinical carcinoma tissue demonstrated its ability to faithfully mimic the native tumor microenvironment. Overall, our findings underscore the utility of the folding paper system as a valuable tool for investigating and identifying critical molecular pathways involved in cancer metastasis.

Whether cancer cells metastasize from the primary site to the distant sites via the lymphatic vessels or the blood vessels directly into the circulation is still under intense study. In this review article, we follow the journey of cancer cells metastasizing to the sentinel lymph nodes and beyond to the distant sites. We emphasize cancer heterogeneity and microenvironment as major determinants of cancer metastasis. Multiple molecules have been found to be associated with the complicated process of metastasis. Based on the large sentinel lymph node data, it is reasonable to conclude that cancer cells may metastasize through the blood vessels in some cases but in most cases, they use the sentinel lymph nodes as the major gateway to enter the circulation to distant sites.