Regulation Of Cancer Metastasis Research Articles

Extracellular vesicles regulate metastable phenotypes of lymphangioleiomyomatosis cells via shuttling ATP synthesis to pseudopodia and activation of integrin adhesion complexes.

Pulmonary lymphangioleiomyomatosis (LAM) is metastatic sarcoma but mechanisms regulating LAM metastasis are unknown. Extracellular vesicle (EV) regulate cancer metastasis but their roles in LAM have not yet been investigated. Here, we report that EV biogenesis is increased in LAM and LAM EV cargo is enriched with lung tropic integrins, metalloproteinases, and cancer stem cell markers. LAM-EV increase LAM cell migration and invasion via the ITGα6/β1-c-Src-FAK-AKT axis. Metastable (hybrid) phenotypes of LAM metastasizing cells, pivotal for metastasis, are regulated by EV from primary tumor or metastasizing LAM cells via shuttling ATP synthesis to cell pseudopodia or activation of integrin adhesion complex, respectively. In mouse models of LAM, LAM-EV increase lung metastatic burden through mechanisms involving lung extracellular matrix remodeling. Collectively, these data provide evidence for the role of EV in promoting LAM lung metastasis and identify novel EV-dependent mechanisms regulating metastable phenotypes of tumor cells. Clinical impact of research is that it establishes LAM pathway as novel target for LAM therapy.

Epigenetic Modifiers in Cancer Metastasis.

Metastasis is the primary cause of cancer-related death, with the dissemination and colonization of primary tumor cells at the metastatic site facilitated by various molecules and complex pathways. Understanding the biological mechanisms underlying the metastatic process is critical for the development of effective interventions. Several epigenetic modifications have been identified that play critical roles in regulating cancer metastasis. This review aims to provide a comprehensive summary of recent advances in understanding the role of epigenetic modifiers, including histone modifications, DNA methylation, non-coding RNAs, enhancer reprogramming, chromatin accessibility, and N6-methyladenosine, in metastasis-associated processes, such as epithelial-mesenchymal transition (EMT), cancer cell migration, and invasion. In particular, this review provides a detailed and in-depth description of the role of crosstalk between epigenetic regulators in tumor metastasis. Additionally, we explored the potential and limitations of epigenetics-related target molecules in the diagnosis, treatment, and prognosis of cancer metastasis.

Comparative analyses of gene networks mediating cancer metastatic potentials across lineage types.

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.

LncRNA SNHG26 promotes gastric cancer progression and metastasis by inducing c-Myc protein translation and an energy metabolism positive feedback loop

Metastasis is a bottleneck in cancer treatment. Studies have shown the pivotal roles of long noncoding RNAs (lncRNAs) in regulating cancer metastasis; however, our understanding of lncRNAs in gastric cancer (GC) remains limited. RNA-seq was performed on metastasis-inclined GC tissues to uncover metastasis-associated lncRNAs, revealing upregulated small nucleolar RNA host gene 26 (SNHG26) expression, which predicted poor GC patient prognosis. Functional experiments revealed that SNHG26 promoted cellular epithelial–mesenchymal transition and proliferation in vitro and in vivo. Mechanistically, SNHG26 was found to interact with nucleolin (NCL), thereby modulating c-Myc expression by increasing its translation, and in turn promoting energy metabolism via hexokinase 2 (HK2), which facilitates GC malignancy. The increase in energy metabolism supplies sufficient energy to promote c-Myc translation and expression, forming a positive feedback loop. In addition, metabolic and translation inhibitors can block this loop, thus inhibiting cell proliferation and mobility, indicating potential therapeutic prospects in GC.

Abstract 1276: Kindlin-2: a novel target of Parkin regulating cancer metastasis

Abstract Although targeted therapies in prostate cancer have clinically shown successful outcomes, resistance to these therapies and acquisition of lineage plasticity pose challenges for fully treating prostate cancer. Among several microscopic perspectives to solve these obstacles, much evidence has emerged indicating that mitochondria dynamics are closely associated with tumor metastasis and tumor progression in various types of cancer. The E3 ubiquitin ligase Parkin is associated with PINK1-mediated mitophagy, allowing cells to control mitochondria damages and generate the needed energy to survive in harsh physiological conditions. Interestingly, we found that Parkin potentially ubiquitinates proteins independently of PINK1-associated mitophagy. By SALIC analysis, we found that K681 and K582 of Kindlin-2 is one of the potential ubiquitination sites by Parkin in prostate cancer cells. Kindlin-2 is a cytoskeletal membrane protein and is a component of the focal adhesion complex. Computational modeling suggested that N-terminal region of Kindlin-2 binds to Parkin, with K581 and K582 of Kindlin-2 exposed outside for ubiquitination. Our studies showed that Kindlin-2 is ubiquitinated and degraded by wild-type Parkin but not by the catalytic site, C431S, mutant Parkin. Furthermore, K581A and K582A mutant Kindlin-2 did not exhibit poly-ubiquitination under conditions of Parkin overexpression. Surprisingly, in our immunofluorescence study, Kindlin-2 was recruited to the mitochondria and co-localized with Parkin. From a mitochondrial functional perspective, wild-type Kindlin-2 reduced mitochondria dynamics, whereas mutant Kindlin-2 didn’t in the presence of Parkin. This suggests that the cytoskeletal protein Kindlin-2 might play a role in mitochondrial dynamics that mediates tumor metastasis. Wild-type Kindlin-2 reduced both focal adhesion generation and decay, unlike mutant Kindlin-2 under Parkin-induced condition. Additionally, this pattern was observed in the single cell lamellipodia dynamics through live cell imaging. 2D and 3D cell invasive assays supported the evidence that Parkin decreases tumor metastatic potential by ubiquitinating Kindlin-2 and regulating mitochondria and focal adhesion dynamics. Our findings indicate that Parkin reduces tumor metastatic potential by ubiquitinating Kindlin-2 and demonstrate the possibility as a therapeutic agent for advanced and immune suppressive tumors. Furthermore, Parkin could be a promising agent for Parkin suppressed tumor patients in line with personalized cancer therapy development. Citation Format: Minjeong Yeon, Irene Bertolini, Dario C. Altieri. Kindlin-2: a novel target of Parkin regulating cancer 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 1276.

A glimpse into novel acylations and their emerging role in regulating cancer metastasis.

Metastatic cancer is a major cause of cancer-related mortality; however, the complex regulation process remains to be further elucidated. A large amount of preliminary investigations focus on the role of epigenetic mechanisms in cancer metastasis. Notably, the posttranslational modifications were found to be critically involved in malignancy, thus attracting considerable attention. Beyond acetylation, novel forms of acylation have been recently identified following advances in mass spectrometry, proteomics technologies, and bioinformatics, such as propionylation, butyrylation, malonylation, succinylation, crotonylation, 2-hydroxyisobutyrylation, lactylation, among others. These novel acylations play pivotal roles in regulating different aspects of energy mechanism and mediating signal transduction by covalently modifying histone or nonhistone proteins. Furthermore, these acylations and their modifying enzymes show promise regarding the diagnosis and treatment of tumors, especially tumor metastasis. Here, we comprehensively review the identification and characterization of 11 novel acylations, and the corresponding modifying enzymes, highlighting their significance for tumor metastasis. We also focus on their potential application as clinical therapeutic targets and diagnostic predictors, discussing the current obstacles and future research prospects.

Miltirone suppresses ESCC cell viability and invasion by promoting E3 ligase mediated‐FZD2 ubiquitination and degradation

AbstractEsophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer and lacks effective treatment. A growing number of studies have confirmed that Frizzled class receptor 2 (FZD2), a receptor for Wnts, regulates cancer metastasis in cancers. This study aims to reveal the anti‐metastatic activity of miltirone on ESCC cells and its mechanism on FZD2 in vitro. Cell‐counting‐kit‐8 (CCK‐8) was used to detect the effect of miltirone on cell growth in ESCC cells. The invasion of ESCC cells was detected by wound healing and transwell assay. Immunofluorescence staining was used to detect the expressions of epithelial‐mesenchymal transition (EMT) markers and the location of FZD2. Western blot and quantitative polymerase chain reaction (q‐PCR) were used to detect levels of target genes, and FZD2 ubiquitination was detected by the co‐immunoprecipitation method. The levels of roof plate‐specific spondins (RSPO1‐4) in cells were determined by ELISA, q‐PCR, and western blot assays. Miltirone exhibits its strongest cytotoxicity with IC50 values of 6.80 μM and 8.43 μM for K30 and K150 cells, respectively. Miltirone inhibited the cell viability and expression of EMT markers, affecting the invasion ability of ESCC, attenuated the Wnt2/FZD2 pathway, and down‐regulated the level of FZD2, which is regulated by the ubiquitination of E3 ubiquitin ligase. Furthermore, we found that miltirone could reduce the expression of RSPO1, and RSPO2, increasing E3 protein levels, and promoting FZD2 ubiquitination, leading to the ubiquitination and subsequent degradation of FZD2. Collectively, our results revealed that miltirone might be a promising drug for the treatment of ESCC, at least partly through regulation of the FZD2 ubiquitination.

ADAMTS Proteases: Their Multifaceted Role in the Regulation of Cancer Metastasis.

Cancer leads to nearly 10 million deaths worldwide per year. The tumour microenvironment (TME) is fundamental for tumour growth and progression. A key component of the TME, the extracellular matrix (ECM) has recently become a focus of interest in cancer research. Dysregulation of ECM synthesis and proteolysis leads to uncontrolled tumour growth and metastasis. Matrix remodelling enzymes, secreted by cancer cells and stromal cells, modify the overall structure and organisation of ECM proteins, therefore influencing biochemical interactions, tissue integrity and tissue turnover. While A Disintegrin and Metalloproteinases (ADAMs)' and matrix metalloproteinases' role in cancer has been deeply investigated, other proteolytic enzymes, like ADAMs with thrombospondin(-like) motifs (ADAMTSs) have been gaining interest due to their roles in modulating cancer cell-ECM interactions and oncogenic signalling pathways. In this review, we will discuss the dysregulation of ADAMTSs in cancer and their roles in regulating cancer development and progression, via ECM remodelling and cell signalling modulation.

Biophysical interplay between extracellular matrix remodeling and hypoxia signaling in regulating cancer metastasis.

Mechanical properties of the tumor microenvironment play a critical role in cancer progression by activation of cancer mechano-responses. The biophysical interactions between cancer cells and their dynamic microenvironment are attributed to force-dependent alterations in molecular pathways that trigger the structural reorganization of intracellular organelles and their associated genetic modifications. Recent studies underscore the role of oxygen concentration in cancer metastasis. Suppressed oxygen levels promote the development of invasive phenotypes and aggressive proliferation of cancer cells, accompanied by remodeling of tumor microenvironment encompassing the modulation of physical settings of extracellular matrix. This review summarizes the role of biophysical interactions between cancer cells and their surroundings in determining cancer progression. Biophysical interpretation of the tumor microenvironment and cancer progression could provide further insights into the development of novel biomedical technologies for therapeutic cancer treatment.

Ferroptosis in Cancer Progression.

Ferroptosis is a newly discovered iron-dependent form of regulated cell death driven by phospholipid peroxidation and associated with processes including iron overload, lipid peroxidation, and dysfunction of cellular antioxidant systems. Ferroptosis is found to be closely related to many diseases, including cancer at every stage. Epithelial-mesenchymal transition (EMT) in malignant tumors that originate from epithelia promotes cancer-cell migration, invasion, and metastasis by disrupting cell-cell and cell-cell matrix junctions, cell polarity, etc. Recent studies have shown that ferroptosis appears to share multiple initiators and overlapping pathways with EMT in cancers and identify ferroptosis as a potential predictor of various cancer grades and prognoses. Cancer metastasis involves multiple steps, including local invasion of cancer cells, intravasation, survival in circulation, arrest at a distant organ site, extravasation and adaptation to foreign tissue microenvironments, angiogenesis, and the formation of "premetastatic niche". Numerous studies have revealed that ferroptosis is closely associated with cancer metastasis. From the cellular perspective, ferroptosis has been implicated in the regulation of cancer metastasis. From the molecular perspective, the signaling pathways activated during the two events interweave. This review briefly introduces the mechanisms of ferroptosis and discusses how ferroptosis is involved in cancer progression, including EMT, cancer angiogenesis, invasion, and metastasis.

Long non-coding RNAs modulate tumor microenvironment to promote metastasis: novel avenue for therapeutic intervention.

Cancer is a devastating disease and the primary cause of morbidity and mortality worldwide, with cancer metastasis responsible for 90% of cancer-related deaths. Cancer metastasis is a multistep process characterized by spreading of cancer cells from the primary tumor and acquiring molecular and phenotypic changes that enable them to expand and colonize in distant organs. Despite recent advancements, the underlying molecular mechanism(s) of cancer metastasis is limited and requires further exploration. In addition to genetic alterations, epigenetic changes have been demonstrated to play an important role in the development of cancer metastasis. Long non-coding RNAs (lncRNAs) are considered one of the most critical epigenetic regulators. By regulating signaling pathways and acting as decoys, guides, and scaffolds, they modulate key molecules in every step of cancer metastasis such as dissemination of carcinoma cells, intravascular transit, and metastatic colonization. Gaining a good knowledge of the detailed molecular basis underlying lncRNAs regulating cancer metastasis may provide previously unknown therapeutic and diagnostic lncRNAs for patients with metastatic disease. In this review, we concentrate on the molecular mechanisms underlying lncRNAs in the regulation of cancer metastasis, the cross-talk with metabolic reprogramming, modulating cancer cell anoikis resistance, influencing metastatic microenvironment, and the interaction with pre-metastatic niche formation. In addition, we also discuss the clinical utility and therapeutic potential of lncRNAs for cancer treatment. Finally, we also represent areas for future research in this rapidly developing field.

Mechanostimulation-induced integrin αvβ6 and latency associated peptide coupling activates TGF-β and regulates cancer metastasis and stemness

The existence of cancer stem cells is the single most important factor contributing to cancer recurrence, and despite immense therapeutic relevance, little research has been done on investigating their origin. Through mechanotransduction, cells translate biophysical cues to biochemical signals. However, little is known about its role in acquisition of cancer stem cell characteristics in non-stem cells. Here, highly ordered nanoenvironments are engineered as models to induce mechanotransduction in cancer cells and elucidate how cell environment delivers precise physical cues via mechanotransduction to modulate expression and localization of key mesenchymal markers to induce epithelial-mesenchymal transition (EMT) and regulate cancer stemness. By initiating integrin αVβ6 and Latency associated peptide (LAP) interactions, cell nanoenvironment mechanically activates TGF-β canonical and non-canonical signaling pathways and induces Epithelial-Mesenchymal transition in U2OS osteosarcoma cells. As a consequence of TGF-β mechanical activation, a synchronous regulation in cancer stem-cell and pluripotency biomarkers is also observed which transcends to formation of cell organoids, a characteristic of cancer stem cells. Furthermore, nanoenvironment-derived cells promote tumor growth and metastasis in-vivo. Mechanistically, RNA-sequencing, RNA-interference and protein translocation experiments establish that cell nanoenvironment plays a decisive role in imparting stemness abilities to incoming cells via EMT and reveals how cells can exploit mechanical sensing to orchestrate tumorigenicity.

Reactive myelopoiesis and FX-expressing macrophages triggered by chemotherapy promote cancer lung metastasis.

Several preclinical studies have demonstrated that certain cytotoxic drugs enhance metastasis, but the importance of host responses triggered by chemotherapy in regulating cancer metastasis has not been fully explored. Here, we showed that multidose gemcitabine (GEM) treatment promoted breast cancer lung metastasis in a transgenic spontaneous breast cancer model. GEM treatment significantly increased accumulation of CCR2+ macrophages and monocytes in the lungs of tumor-bearing as well as tumor-free mice. These changes were largely caused by chemotherapy-induced reactive myelopoiesis biased toward monocyte development. Mechanistically, enhanced production of mitochondrial ROS was observed in GEM-treated BM Lin-Sca1+c-Kit+ cells and monocytes. Treatment with the mitochondria targeted antioxidant abrogated GEM-induced hyperdifferentiation of BM progenitors. In addition, GEM treatment induced upregulation of host cell-derived CCL2, and knockout of CCR2 signaling abrogated the pro-metastatic host response induced by chemotherapy. Furthermore, chemotherapy treatment resulted in the upregulation of coagulation factor X (FX) in lung interstitial macrophages. Targeting activated FX (FXa) using FXa inhibitor or F10 gene knockdown reduced the pro-metastatic effect of chemotherapy. Together, these studies suggest a potentially novel mechanism for chemotherapy-induced metastasis via the host response-induced accumulation of monocytes/macrophages and interplay between coagulation and inflammation in the lungs.

Mass cytometry analysis of mouse nonclassical monocyte heterogeneity in breast tumors

Abstract Monocytes have emerged as important regulators of cancer progression. Our previous studies demonstrated the importance of nonclassical Ly6C lomonocytes in regulating cancer metastasis in mouse models. Here, we aimed to study monocyte heterogeneity in two different breast cancer tumors in mice using either 4T1 or EMT6 cells. 4T1 tumors exhibit an increased ability to metastasize in the lung in a BALB/c mouse breast cancer model compared to the less aggressive EMT6 tumor model. We evaluated 35 surface markers of tumor-infiltrated monocytes and dendritic cells in tumors isolated from each model using CyTOF mass cytometry. Analysis of monocytes and dendritic cells in the tumors using the Seurat package and the FlowSom algorithm identified 12 cell subsets. Significant differences were discovered between the two tumor types in frequencies of four of 12 identified subsets. However, only one of these subsets, a nonclassical monocyte subset, was higher in the less metastatic EMT6 tumors. This subset was 5-fold higher in EMT6 tumors versus more aggressive 4T1 tumors. This Ly6C lononclassical monocyte subset showed high expression of CD169 and CX3CR1, CD86 and CD80. These differentially expressed markers suggest a functional importance in this subset in migration to the tumor and antigen presentation, both of which are anti-tumoral functions. Ongoing studies are aimed towards understanding the role of this non-classical monocyte population in regulating breast cancer metastasis. This work was supported by NIH R01 CA202987, and P01 HL136275

Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis

Epithelial to mesenchymal transition (EMT) plays a crucial role in cancer metastasis, accompanied with vast epigenetic changes. AMP-activated protein kinase (AMPK), a cellular energy sensor, plays regulatory roles in multiple biological processes. Although a few studies have shed light on AMPK regulating cancer metastasis, the inside epigenetic mechanisms remain unknown. Herein we show that AMPK activation by metformin relieves the repressive H3K9me2-mediated silencing of epithelial genes (e.g., CDH1) during EMT processes and inhibits lung cancer metastasis. PHF2, a H3K9me2 demethylase, was identified to interact with AMPKα2. Genetic deletion of PHF2 aggravates lung cancer metastasis and abolishes the H3K9me2 downregulation and anti-metastasis effect of metformin. Mechanistically, AMPK phosphorylates PHF2 at S655 site, enhancing PHF2 demethylation activity and triggering the transcription of CDH1. Furthermore, the PHF2-S655E mutant that mimics AMPK-mediated phosphorylation status further reduces H3K9me2 and suppresses lung cancer metastasis, while PHF2-S655A mutant presents opposite phenotype and reverses the anti-metastasis effect of metformin. PHF2-S655 phosphorylation strikingly reduces in lung cancer patients and the higher phosphorylation level predicts better survival. Altogether, we reveal the mechanism of AMPK inhibiting lung cancer metastasis via PHF2 mediated H3K9me2 demethylation, thereby promoting the clinical application of metformin and highlighting PHF2 as the potential epigenetic target in cancer metastasis.

The tumor-immune ecosystem in shaping metastasis.

A better understanding of the mechanisms regulating cancer metastasis is critical to develop new therapies and decrease mortality. Emerging evidence suggests that the interactions between tumor cells and the host immune system play important roles in establishing metastasis. Tumor cells are able to recruit immune cells, which in turn promotes tumor cell invasion, intravasation, survival in circulation, extravasation, and colonization in different organs. The tumor-host immunological interactions also generate a premetastatic niche in distant organs which facilitates metastasis. In this review, we summarize the recent findings on how tumor cells and immune cells regulate each other to coevolve and promote the formation of metastases at the major organ sites of metastasis.

Activated Leukocyte Cell Adhesion Molecule (ALCAM), a Potential ‘Seed’ and ‘Soil’ Receptor in the Peritoneal Metastasis of Gastrointestinal Cancers

Activated Leukocyte Cell Adhesion Molecule (ALCAM/CD166) is a cell-cell adhesion protein conferring heterotypic and homotypic interactions between cells of the same type and different types. It is aberrantly expressed in various cancer types and has been shown to be a regulator of cancer metastasis. In the present study, we investigated potential roles of ALCAM in the peritoneal transcoelomic metastasis in gastrointestinal cancers, a metastatic type commonly occurred in gastro-intestinal and gynaecological malignancies and resulting in poor clinical outcomes. Specifically, we studied whether ALCAM acts as both a 'seed' receptor in these tumour cells and a 'soil' receptor in peritoneal mesothelial cells during cancer metastasis. Gastric cancer and pancreatic cancer tissues with or without peritoneal metastasis were compared for their levels of ALCAM expression. The impact of ALCAM expression in these tumours was also correlated to the patients' clinical outcomes, namely peritoneal metastasis-free survival. In addition, cancer cells of gastric and pancreatic origins were used to create cell models with decreased or increased levels of ALCAM expression by genetic knocking down or overexpression, respectively. Human peritoneal mesothelial cells were also genetically transfected to generate cell models with different profiles of ALCAM expression. These cell models were used in the tumour-mesothelial interaction assay to assess if and how the interaction was influenced by ALCAM. Both gastric and pancreatic tumour tissues from patients who developed peritoneal metastases had higher levels of ALCAM transcript than those without. Patients who had tumours with high levels of ALCAM had a much shorter peritoneal metastasis free survival compared with those who had low ALCAM expression (p = 0.006). ALCAM knockdown of the mesothelial cell line MET5A rendered the cells with reduced interaction with both gastric cancer cells and pancreatic cancer cells. Likewise, levels of ALCAM in both human gastric and pancreatic cancer cells were also a determining factor for their adhesiveness to mesothelial cells, a process that was likely to be triggered the phosphorylation of the SRC kinase. A soluble ALCAM (sALCAM) was found to be able to inhibit the adhesiveness between cancer cells and mesothelial cells, mechanistically behaving like a SRC kinase inhibitor. ALCAM is an indicator of peritoneal metastasis in both gastric and pancreatic cancer patients. It acts as not only a potential peritoneal 'soil' receptor of tumour seeding but also a 'soil' receptor in peritoneal mesothelial cells during cancer metastasis. These findings have an important therapeutic implication for treating peritoneal transcoelomic metastases.

Emerging roles of long noncoding and circular RNAs in pancreatic ductal adenocarcinoma

An international project on the human genome revealed that various RNAs (e.g., messenger RNAs, microRNAs, and long noncoding RNAs [lncRNAs] and their subclass circular RNA [circRNA)) are involved in the pathogenesis of different human diseases, including cancer. Recent studies have highlighted the critical roles of lncRNAs and circRNA in pancreatic ductal adenocarcinoma (PDAC), especially in the epithelial-mesenchymal transition, a phenomenon regulating cancer metastasis. Growing research in this field has indicated that the tertiary structure of lncRNAs supposedly regulates biological function via RNA-RNA or RNA-protein associations, aiding early diagnosis and therapy selection for various diseases, including cancer. Here we describe the emerging roles of ncRNAs in PDAC and highlight how these ncRNAs can be used to detect and control this intractable cancer.

Gastric cancer cell-derived extracellular vesicles disrupt endothelial integrity and promote metastasis

The endothelium is the critical barrier that controls transendothelial communications. Blood vessels in cancer tissue are poorly developed and highly permeable. However, it is poorly understood how circulating cancer cells released through these “leaky” vessels break the intact vasculature of remote organs to metastasize. We investigated the roles of cancer cell-derived extracellular vesicles (CEVs) in regulating cancer metastasis by analyzing samples from gastric cancer patients, performing in vitro experiments, and studying mouse models. We made several novel observations. First, the rate of metastasis was closely associated with plasma levels of CEVs in patients with gastric cancer. Second, cultured endothelial cells endocytosed CEVs, resulting in cytoskeletal rearrangement, low expression of the junction proteins cadherin and CD31, and forming large intercellular gaps to allow the transendothelial migration of cancer cells. The dynamin inhibitor Dynasore prevented these CEV-induced changes of endothelial cells by blocking CEVs endocytosis. Third, CEVs disrupted the endothelial barrier of cancer-bearing mice to promote cancer metastasis. Finally, lactadherin promoted the clearance of circulating CEVs to reduce metastasis. These results demonstrate the essential role of CEVs in promoting the metastasis of gastric cancer.

Emerging Regulatory Mechanisms of N6-Methyladenosine Modification in Cancer Metastasis.

Cancer metastasis is the major cause of cancer-related deaths and accounts for poor therapeutic outcomes. A metastaticcascadeis a series of complicated biological processes. N6-methyladenosine (m6A) is the most abundant and conserved epitranscriptomic modification in eukaryotic cells, which has great impacts on RNA production and metabolism, including RNA splicing, processing, degradation and translation. Accumulating evidence demonstrates that m6A plays a critical role in regulating cancer metastasis. However, there is a lack of studies that review the recent advances of m6A in cancer metastasis. Here, we systematically retrieved the functions and mechanisms of how the m6A axis regulates metastasis, and especially summarized the organ-specific liver, lung and brain metastasis mediated by m6A in various cancers. Moreover, we discussed the potential application of m6A modification in cancer diagnosis and therapy, as well as the present limitations and future perspectives of m6A in cancer metastasis. This review provides a comprehensive knowledge on the m6A-mediated regulation of gene expression, which is helpful to extensively understand the complexity of cancer metastasis from a new epitranscriptomic point of view and shed light on the developing novel strategies to anti-metastasis based on m6A alteration.