Invasive Behavior Research Articles

Sober: Explores for invasive behaviour of malware

Trigger-based malware samples exhibit untrustworthy aims provided that certain environmental conditions are satisfied. We have categorized trigger-based malware behaviours into two classes, i.e., invasive and evasive. Invasive behaviour is concerned with malicious activities, while malware uses evasive behaviours for self-defence. In this article, we propose a greedy incremental approach for detecting invasive trigger-based malicious behaviour. The method proceeds by identifying and supplying resources required by malign samples. Trigger-based behaviours vary depending on environmental conditions. Such behaviours can be modelled as directed graphs, where each node represents a state, and edges denote invocation of a specific event. We define each state in the graph as atomic behaviour, represented using API calls, having legitimate functionality. This atomic behaviour transforms into harmful action if augmented with additional APIs. A well-known challenge with behavioural analysis is the proactive identification of malicious activities before devices are compromised. Timely prediction of malicious behaviours without damaging the systems can be fulfilled by defining them as atomic actions. To reckon a sub-behaviour as atomic, we propose a novel algorithm. Besides, a new likelihood statistical significance test, Htest, is suggested to extract frequent subgraphs of graphs, representing malware family signature. The main message underlying Htest is that the lesser the number of subgraphs exhibiting benign behaviour, the higher the chances of the sub-graph being chosen as malware family signature. Experiments conducted on 2320 real malware samples demonstrate a 42% reduction in the number of signatures than the state-of-the-art methods, namely CDG and CMQDG. Also, 3% and 1.3% improvement in path coverage compared to the state-of-the-art methods, namely Pytrigger and GoldenEye.

Exploring the role of the tumor microenvironment in refractory pituitary tumor pathogenesis.

Treatment-refractory pituitary tumors demonstrate characteristics resembling those of highly aggressive tumors, in which the local tumor microenvironment (TME) plays a dominant role in promoting aggressiveness and refractoriness. However, role of the TME in pituitary tumors is not well studied. Literature on the TME and development of refractory pituitary tumors was reviewed RESULTS: TME harbors tumorigenic immune cells, cancer-associated fibroblasts (CAF), extracellular matrix, and other factors that have been shown to affect behavior of tumor tissue. For example, tumor-associated macrophages and tumor-infiltrating lymphocytes correlate with aggressive and invasive tumor behavior in nonfunctioning and growth hormone-secreting (GH) pituitary tumors, while CAF release of TGFβ, FGF2, cytokines, chemokines, and growth factors may promote treatment resistance, tumor fibrosis, and inflammation in prolactinomas and GH-secreting tumors. In turn, Wnt pathway activation can further promote cell growth in dopamine-resistant prolactinomas. Finally, proteins secreted by extracellular matrix are associated with increased angiogenesis in invasive tumors. It is likely that multiple mechanisms, including TME, contribute to the development of aggressive refractory pituitary tumors. Given the increased morbidity and mortality associated with pituitary tumor refractoriness, more research on the role of TME is warranted.

Bacterial and Viral Pathogens with One Health Relevance in Invasive Raccoons (Procyon lotor, Linné 1758) in Southwest Germany.

In Europe, raccoons are invasive neozoons with their largest population in Germany. Globally, this mesocarnivore acts as a wildlife reservoir for many (non-)zoonotic (re-)emerging pathogens, but very little epidemiological data is available for southwest Germany. This exploratory study aimed to screen free-ranging raccoons in Baden-Wuerttemberg (BW, Germany) for the occurrence of selected pathogens with One Health relevance. Organ tissue and blood samples collected from 102 animals, obtained by hunters in 2019 and 2020, were subsequently analysed for two bacterial and four viral pathogens using a qPCR approach. Single samples were positive for the carnivore protoparvovirus-1 (7.8%, n = 8), canine distemper virus (6.9%, n = 7), pathogenic Leptospira spp. (3.9%, n = 4) and Anaplasma phagocytophilum (15.7%, n = 16). West Nile virus and influenza A virus were not detected. Due to their invasive behaviour and synanthropic habit, raccoons may increase the risk of infections for wildlife, domestic animals, zoo animals and humans by acting as a link between them. Therefore, further studies should be initiated to evaluate these risks.

Thoughts of treatment of tumor diseases based on toxic pathogen theory

The toxic pathogen theory, an important part of the theories of traditional Chinese medicine(TCM), began in the Qin and Han dynasties, formed in the Jin, Sui, Tang, and Song dynasties, developed rapidly in the Ming and Qing dynasties, and conti-nued to develop in contemporary times based on the achievements of its predecessors. The continuous exploration, practice, and inheri-tance of many medical practitioners over the generations have facilitated the enrichment of its connotation. The toxic pathogen is violent, fierce, dangerous, prolonged, rapid in transmission, easy to hurt the internal organs, hidden, and latent, with many changes, and it is closely related to the development of tumor diseases. TCM has a history of thousands of years in the prevention and treatment of tumor diseases. It is gradually realized that the etiology of tumor is mainly attributed to the deficiency of healthy Qi and excess of to-xic pathogen, and the struggle between healthy Qi and toxic pathogen runs through the whole course of tumor, with the deficiency of healthy Qi as the prerequisite and the invasion of toxic pathogen as the root of the occurrence. The toxic pathogen has a strong carcinogenic effect and is involved in the whole process of tumor development, which is closely related to the malignant behaviors of tumors, including proliferation, invasion, and metastasis. This study discussed the historical origin and modern interpretation of the toxic pathogen theory in the prevention and treatment of tumors, with aims of sorting out the theoretical system based on the toxic pathogen theory in the treatment of tumor diseases, and illustrating the importance of the toxic pathogen theory in the treatment of tumors in the context of modern research on pharmacological mechanisms and the development and marketing of relevant anti-tumor Chinese medicinal preparations.

Epidemiology and risk stratification of low-grade gliomas in the United States, 2004-2019: A competing-risk regression model for survival analysis.

Understanding the epidemiology and prognostic factors of low-grade gliomas (LGGs) can help estimate the public health impact and optimize risk stratification and treatment strategies. 3 337 patients diagnosed with LGGs were collected from the Surveillance, Epidemiology, and End Results (SEER) dataset, 2004-2019. The incidence trends of LGGs were analyzed by patient demographics (sex, age, race, and ethnicity). In addition, a competing risk regression model was used to explore the prognostic factors of LGGs by patient demographics, tumor characteristics (histological subtypes, invasiveness, and size), treatment modality, and molecular markers (IDH mutation and 1p/19q codeletion). LGGs occurred more frequently in male, non-Hispanic, and White populations. The incidence rate of mixed gliomas was stable from 2004 to 2013 and decreased dramatically to nearly zero until 2019. The risk of death increased 1.99 times for every 20-year increase in patient age, and 60 years is a predictive cut-off age for risk stratification of LGGs. Male patients showed poorer LGG-specific survival. Among the different subtypes, astrocytoma has the worst prognosis, followed by mixed glioma and oligodendroglioma. Tumors with larger size (≥5 cm) and invasive behavior tended to have poorer survival. Patients who underwent gross total resection had better survival rates than those who underwent subtotal resection. Among the different treatment modalities, surgery alone had the best survival, followed by surgery + radiotherapy + chemotherapy, but chemotherapy alone had a higher death risk than no treatment. Furthermore, age, invasiveness, and molecular markers were the most robust prognostic factors. This study reviewed the incidence trends and identified several prognostic factors that help clinicians identify high-risk patients and determine the need for postoperative treatment according to guidelines.

Mucinous Cystic Neoplasms of the Liver: Epidemiology, Diagnosis, and Management.

Mucinous cystic neoplasms (MCNs) are rare tumors of the liver, occasionally seen in the biliary tree. Epidemiologic data are limited by their indolence and recent changes to diagnostic criteria. They are considered premalignant lesions capable of invasive behavior. While their etiology remains unknown, their female predominance, age of onset, and hormonally responsive ovarian-type stroma suggest ectopic organogenesis during embryologic development. MCNs can typically be recognized on imaging; yet, invasiveness is often indeterminate, and percutaneous tissue biopsy has shown limited value. Therefore, complete excision is recommended for all lesions as focal malignant transformation and metastatic disease has been reported.

Comprehensive analysis ofCDK5 as a novel biomarker for progression in esophageal cancer.

Cyclin-dependent kinase 5 (CDK5) is a member of the cyclin-dependent kinase family, and unlike the rest of the members of the family, its kinase activity is independent of cyclins. Accumulating evidence has shown that CDK5 plays a significant role in the progress of tumorigenesis except in nervous system. In particular, the expression of CDK5 and its function in esophageal cancer (ESCA) remain unknown. With TCGA and GEO databases, CDK5 was analyzed with the expression, predicted value, clinical relationship, functional enrichment, immune cell infiltration and immune molecules in ESCA. In addition, we explored the CDK5 expression with local datasets and the influence of CDK5 on proliferation, migration and invasion behaviors of the esophageal squamous cell carcinoma (ESCC) cells in vitro and in vivo experiments. CDK5 expression was upregulated in ESCA, and this regulation has been verified in cell lines of ESCC. Further analysis has found that the expression of CDK5 was correlated with race, weight, BMI, histological type and tumor central location in ESCA. KEGG analysis revealed that CDK5 was involved in the progress of cancers, innate immune system and PI3K-Akt signaling pathway. CDK5 was closely related to immune cells and immune molecules in ESCA. Functional experiments confirmed CDK5 was an oncogene in ESCC by in vivo and in vitro models. This study shows that CDK5 is a risk factor to promote tumor progression, and Roscovitine could be one of the effective tools in the therapy of ESCA.

Targeting mTOR Pathway in PTEN Deleted Newly Isolated Chordoma Cell Line.

Chordomas are rare primary malignant tumours of notochordal origin usually arising along the axial skeleton with particular predilection of the skull base and sacrococcygeal region. Albeit usually slow-growing, chordomas can be aggressive mostly depending on their invasive behaviour and according to different histotypes and molecular alterations, including TBXT duplication and SMARCB1 homozygous deletion. Partial or complete PTEN deficiency has also been observed. PTEN is a negative regulator of the Akt/mTOR pathway and hyperactivation of Akt/mTOR in cells lacking PTEN expression contributes to cell proliferation and invasiveness. This pathway is targeted by mTOR inhibitors and the availability of in vitro models of chordoma cells will aid in further investigating this issue. However, isolation and maintenance of chordoma cell lines are challenging and PTEN-deleted chordoma cell lines are exceedingly rare. Hereby, we established and characterized a novel human PTEN-deleted chordoma cell line (CH3) from a primary skull base chordoma. Cells exhibited morphological and molecular features of the parent tumour, including PTEN loss and expression of Brachyury and EMA. Moreover, we investigated the activation of the mTOR pathway and cell response to mTOR inhibitors. CH3 cells were sensitive to Rapamycin treatment suggesting that mTOR inhibitors may represent a valuable option for patients suffering from PTEN-deleted chordomas.

Implication thérapeutique potentielle de la kinase de l’adhérence focale dans le cancer pulmonaire à petites cellules

The molecular steps leading to small cell lung cancer (SCLC) development and progression are still poorly understood, resulting in the absence of targeted therapy and an extremely poor prognosis. Activation of Focal Adhesion Kinase (FAK) plays a key role in the invasive behavior of this cancer in vitro. Our hypothesis is that FAK could be a therapeutic target in SCLC. Our work aims to describe a mouse model to study the role of FAK and the antitumoral potential of its inhibition in SCLC in vivo.

Ultrasound and microbubble-mediated delivery of miR-424-5p has a therapeutic effect in preeclampsia

ObjectiveTo determine the influence of ultrasound/microbubble-mediated miR-424-5p delivery on trophoblast cells and the underlying mechanism.MethodsBlood pressure and 24-h proteinuria of patients with preeclampsia (PE) were measured as well as the levels of miR-424-5p and amine oxidase copper containing 1 (AOC1) in placental tissues. HTR-8/Svneo and TEV-1 cells were subjected to cell transfection or ultrasonic microbubble transfection for determination of the expression of miR-424-5p, AOC1, β-catenin and c-Myc as well as cell proliferation, apoptosis, migration and invasiveness. The concentrations of placental growth factor (PLGF), human chorionic gonadotropin (β-hCG) and tumor necrosis factor-α (TNF-α) were measured in HTR-8/Svneo and TEV-1 cells. RNA immunoprecipitation (RIP) and dual luciferase reporter assay detected the binding of miR-424-5p to AOC1. A PE mouse model was induced by subcutaneous injection of L-NAME, where the influence of ultrasound/microbubble-mediated miR-424-5p delivery was evaluated.ResultsmiR-424-5p was downregulated while AOC1 was upregulated in the placental tissues from PE patients. Overexpression of miR-424-5p activated Wnt/β-catenin signaling pathway and promoted the proliferation of HTR-8/Svneo and TEV-1 cells as well as enhanced the migratory and invasive behaviors. AOC1 overexpression partly eliminated the effects of miR-424-5p on HTR-8/Svneo and TEV-1 cells. Ultrasound and microbubble mediated gene delivery enhanced the transfection efficiency of miR-424-5p and further promoted the effects of miR-424-5p in trophoblast cells. Ultrasound/microbubble-mediated miR-424-5p delivery alleviated experimental PE in mice.ConclusionUltrasound and microbubble-mediated miR-424-5p delivery targets AOC1 and activates Wnt/β-catenin signaling pathway, thus promoting the aggressive phenotype of trophoblast cells, which indicating that miR-424-5p/AOC1 axis might be involved with PE pathogenesis.

Expression and Clinical Significance of MDM2 in Non-Functioning PitNETs.

Background and Objective: Non-functioning pituitary neuroendocrine tumors (NF-PitNETs) represent a heterogeneous tumor type that lacks effective medical treatment. MDM2, the main negative regulator of p53, binds to and forms a stable complex with p53 to regulate its activity. In this study, we measured the expression levels and role of MDM2 in non-functioning PitNET patients' combined clinical features and investigated the effect of etoposide on the cell bioactivity of the GT1-1 cell line in vivo and in vitro. Methods: RT-PCR and immunochemistry measured the expression levels and role of MDM2 in 103 NF-PitNET patients' combined clinical features. Cell proliferation, migration, colony and apoptosis experiments measured the effect of etoposide on the GT1-1 cell line in vivo and in vitro. Results: There was more invasive behavior (p = 0.013) in patients with high MDM2, who were also younger (p = 0.007), were more frequently female (p = 0.049) and had larger tumor sizes (p = 0.018) compared with patients with low MDM2. Patients with high p53 were younger (p = 0.017) and had larger tumor sizes (p = 0.034) compared with patients with low p53. Univariate (p = 0.018) and multivariate (p = 0.023) Cox regression analysis showed that MDM2 was the independent factor for invasive behavior in NF-PitNET patients. Log-rank analysis showed that the average progression-free survival (PFS) time in the low MDM2 patients was longer than that in the high MDM2 patients (p = 0.044). Functional studies indicated that etoposide inhibited cell proliferation and cell migration and induced apoptosis in p53 independence in GT1-1 cells. Furthermore, etoposide significantly inhibited the growth of GT1-1-xenograft in BALB/c nude mice. The tumor growth inhibition rate of etoposide was 67.4 ± 4.6% after 14 d of treatment, which suggested the anti-tumor activity of etoposide. Conclusions: MDM2 played the role of tumorigenesis of NF-PitNET in a p53 independence manner, and an MDM2 inhibitor could be a potential choice for the treatment of NF-PitNET patients.

Competition of SARS-CoV-2 variants on the pandemic transmission dynamics

SARS-CoV-2 has produced various variants during its ongoing evolution. The competitive behavior driven by the co-transmission of these variants has influenced the pandemic transmission dynamics. Therefore, studying the impact of competition between SARS-CoV-2 variants on pandemic transmission dynamics is of considerable practical importance. In order to formalize the mechanism of competition between SARS-CoV-2 variants, we propose an epidemic model that takes into account the co-transmission of competing variants. The model focuses on how cross-immunity influences the transmission dynamics of SARS-CoV-2 through competitive mechanisms between strains. We found that inter-strain competition affects not only both the final size and the replacement time of the variants, but also the invasive behavior of new variants in the future. Due to the limited extent of cross-immunity in previous populations, we predict that the new strain may infect the largest number of individuals in China without control interventions. Moreover, we also observed the possibility of periodic outbreaks in the same lineage and the possibility of the resurgence of previous lineages. Without the invasion of a new variant, the previous variant (Delta variant) is projected to resurgence as early as 2023. However, its resurgence may be prevented by a new variant with a greater competitive advantage.

The relationship between Invasive Alien Solanum elaeagnifolium Cav. characters and impacts in different habitats

Invasive alien plants are one of the most serious threats to agriculture. The growth traits of Solanum elaeagnifolium Cav. in crops and their demographics in invaded vs non-invaded communities were examined. The majority of S. elaeagnifolium germination was observed in the spring compared to the summer. Five stages were distinguished, which started with a short time of seedling and juvenile stages, extended flowering, and fruiting stages, and seed dispersion in the winter season. An increase in shoots/roots ratio, leaf area ratio and leaf mass fraction during growth with the varied rate was proved. The accumulation coefficient of dry mass exceeded 0.93 and was significant (P > 0.001) with great variability within plant parts, and stage intervals. While the high growth rate is influenced by the stages and habitats. The recipient communities are affected negatively by S. elaeagnifolium invasion which is associated with lower diversity, richness, and evenness vs non-invaded communities. High similarities were found in the invaded area and communities. Finally, high and varied growth and plasticity of S. elaeagnifolium characterized their invasion behavior via different habitats. There were suitable determinants indices of diversity that can be used in the comparison between invaded and non-invaded communities. This knowledge may be useful for use in agro-environment protection and to improve the management methods of invasive alien species.

Action of Photodynamic Therapy at Low Fluence in 9 L/lacZ Cells after Interaction with Chlorins

Gliosarcoma (GS) is a primary malignant neoplasm of the central nervous system, treated with an unfavorable prognosis with surgery, radiotherapy, and chemotherapy. The treatment for GS consists of surgical resection, almost always accompanied by radiotherapy and/or chemotherapy, given the invasive behavior of the tumor. Photodynamic Therapy (PDT) is studied as an alternative method that combines light, a photosensitizer (PS), and molecular oxygen. This study aimed to compare the effects of PDT using the photosensitizers Fotoenticine (FTC) and Photodithazine (PDZ) at low concentrations and fluences. For this study, 9 L/lacZ cells, concentrations of 1.55 µg mL−1, 12.5 µg mL−1, and 50 µg mL−1 of chlorins and fluences of 1, 5, and 10 J/cm2 were used. A test was also carried out with Trypan Blue in L929 cells at the mentioned concentrations at 5 J/cm2. Both chlorins were internalized in the cytoplasm, with a significant reduction in viability (>95%) in almost all groups and altered cell adhesion and morphology after PDT. HSP70 expression decreased in both PS, while HSP27 increased only in PDT with FTC, and although there was a change in cell adhesion in the 9 L/LacZ lineage it was not observed in the L929 fibroblast lineage. Both chlorins were effective, highlighting the concentration of 50 µg mL−1 at the fluence of 5 J/cm2; according to the present study, the PDZ showed better results.

Modeling and simulation of the penetration of a compound droplet into a throat in a pore-throat structure

We present a theoretical and numerical study of a compound droplet flowing through a single pore-throat structure. By quantifying the capillary pressures in the pore and throat under various geometrical conditions, we derive a theoretical model to predict whether the compound droplet is able to penetrate into the throat in a pore-throat structure. Meanwhile, the lattice Boltzmann simulations are conducted to assess the capability and accuracy of the theoretical model. Through a combination of theoretical analysis and lattice Boltzmann simulations, we then investigate the effect of inner droplet size, compound droplet size, and surface wettability on the invasion behavior of a compound droplet. The results show that with increasing the inner droplet size or the compound droplet size, the compound droplet undergoes the transition from the state where the entire compound droplet can pass through the throat to the state where only a part of outer droplet penetrates into and blocks the throat. Although the theoretical predictions show good agreement with the simulation results for most of the cases investigated, it is found that the proposed theoretical model is not applicable to the cases in which the droplets are intermediate-wetting or wetting to the solid surface. This is because the shape of newly formed interface in the pore significantly deviates from the initial circle, which violates the assumption made in the derivation of the theoretical model.

Cancer-associated fibroblasts in a 3D engineered tissue model induce tumor-like matrix stiffening and EMT transition.

There is an increasing need for the use of 3D in vitro models over 2D culture. Yet, most models remain unable to fully reproduce the complexity observed in vivo. Tissue-engineered models based on the self-assembly method have the potential to better recapitulate the stroma architecture, composition, and cell heterogeneity. Here, we used the self-assembly method and a bladder tissue model to engineer a tumor-like environment, and validated its relevance as a cancer model. The bioengineered bladder cancer model was reconstituted using healthy primary fibroblasts (HFs) and a sub-population of induced cancer-associated fibroblast-like cells (iCAFs) along with a normal urothelium overlay. The iCAFs-derived extracellular matrix (ECM) composition was found to be more fibrotic with increased collagen remodeling and altered fibronectin content. Moreover, the average stiffness of the ECM scaffolds produced by the iCAFs was 7.4 kPa compared to 1.3 kPa for those produced by HFs. In line with those results, urothelial cells overlaid on the iCAFs-derived ECM was found to be more contractile. We also observed increased nuclear translocation of the mechanosensor YAP1 in urothelial cells overlaid on these iCAFs-derived ECM. Furthermore, urothelial cells seeded on iCAFs-derived stroma displayed invasive behavior compared to urothelial cells on HFs. As increased ECM stiffness and cell contractility are associated with the epithelial-to-mesenchymal transition (EMT), we showed an increase expression of the mesenchymal EMT markers, vimentin and ZEB1, within the urothelium on the iCAFs-derived ECM. Overall, our tissue-engineered tumor model achieved stiffness levels comparable to those observed in bladder cancers along with CAF-mediated ECM remodeling, while the urothelium displayed the biological responses that would be expected within a tumor-like environment. Future experiments will take advantage of the 3D and in vivo-like properties of our engineered model to investigate tumor cell invasion.

Diplosoma simile (Ascidiacea: Didemnidae) distribution and its photosynthetic thermal stress responses from Mauritius: Implications for invasive or opportunistic behavior

Abstract. Fai ALY, Kaullysing D, Jeetun S, Soondur M, Bhagooli R. 2023. Diplosoma simile (Ascidiacea: Didemnidae) distribution and its photosynthetic thermal stress responses from Mauritius: Implications for invasive or opportunistic behavior. Indo Pac J Ocean Life 7: 16-26. This study aimed to investigate the morphological identity of the ascidian Diplosoma, its distribution, experimental thermal stress responses, and its characteristics of being potentially invasive or opportunistic in Mauritian waters. The Diplosoma species were anesthetized in menthol, fixed, and preserved in a formalin-seawater solution. Isolated zooids and embryos were examined under a microscope for distinct morphological characteristics, which revealed their identity as D. simile (Sluiter, 1909). The D. simile percentage cover studied at seven sites in 2019 around Mauritius tended to be high at the near-reef zone, with a high percentage of dead coral cover per 0.5 m2. At Flic en Flac, long-term observations in 2008, 2010, 2016, and 2019 indicated a significant decrease and increased from 61.25±3.31 to 6.15±0.60 % and 0.08±0.05 to 2.50±090% for the percentage covers of live coral and D. simile, respectively. The D. simile was recorded on five coral species, and its percentage occurrence increased from 2008 to 2019 in Acropora muricata, A. cytherea, Pocillopora damicornis, and Montipora aequituberculata with the highest levels occurring in Acropora while Porites lutea was not found to be covered by D. simile during the study. Visual observations from the thermal exposures at 27ºC, 30ºC, and 33ºC during 19 hrs revealed that D. simile was more affected by increasing temperature and exposure time. Using four observed conditions of normal, bleached/paled, tissue sloughing, and mortality, D. simile suffered from only bleaching/paling at 33ºC at 19 hrs exposure. Variable visual responses were noted for corals, with P. lutea appearing normal at all trials while A. cytherea was suffering from mortality both at 30ºC and 33ºC at 19 hrs exposure. The effective quantum yield (?PSII), measured using a Diving-PAM, declined significantly at 33ºC treatments at 6 and 19 hrs of exposure. D. simile generally tended to be more thermally tolerant than corals like P. lutea, P. damicornis, M. aequituberculata, A. muricata, A, cytherea, though the ?PSII thermal responses were variable among the tested corals. When considering the reported behavioral characteristics of D. simile, namely the lack of broad dispersal range and wide environmental tolerance, it is tempting to deduce that the species is potentially invasive. However, in this study, D. simile’s significant distribution on dead corals, its presence in zones of high anthropogenic activities, and its relatively more robust thermal stress responses than corals colonized suggest an opportunistic behavior.

The interaction of β-arrestin1 with talin1 driven by endothelin A receptor as a feature of α5β1 integrin activation in high-grade serous ovarian cancer

Dissemination of high-grade serous ovarian cancer (HG-SOC) in the omentum and intercalation into a mesothelial cell (MC) monolayer depends on functional α5β1 integrin (Intα5β1) activity. Although the binding of Intα5β1 to fibronectin drives these processes, other molecular mechanisms linked to integrin inside-out signaling might support metastatic dissemination. Here, we report a novel interactive signaling that contributes to Intα5β1 activation and accelerates tumor cells toward invasive disease, involving the protein β-arrestin1 (β-arr1) and the activation of the endothelin A receptor (ETAR) by endothelin-1 (ET-1). As demonstrated in primary HG-SOC cells and SOC cell lines, ET-1 increased Intβ1 and downstream FAK/paxillin activation. Mechanistically, β-arr1 directly interacts with talin1 and Intβ1, promoting talin1 phosphorylation and its recruitment to Intβ1, thus fueling integrin inside-out activation. In 3D spheroids and organotypic models mimicking the omentum, ETAR/β-arr1-driven Intα5β1 signaling promotes the survival of cell clusters, with mesothelium-intercalation capacity and invasive behavior. The treatment with the antagonist of ETAR, Ambrisentan (AMB), and of Intα5β1, ATN161, inhibits ET-1-driven Intα5β1 activity in vitro, and tumor cell adhesion and spreading to intraperitoneal organs and Intβ1 activity in vivo. As a prognostic factor, high EDNRA/ITGB1 expression correlates with poor HG-SOC clinical outcomes. These findings highlight a new role of ETAR/β-arr1 operating an inside-out integrin activation to modulate the metastatic process and suggest that in the new integrin-targeting programs might be considered that ETAR/β-arr1 regulates Intα5β1 functional pathway.

Correlation between the Warburg effect and progression of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is ineligible for hormonal therapy and Her-2-targeted therapy due to the negative expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2. Although targeted therapy and immunotherapy have been shown to attenuate the aggressiveness of TNBC partially, few patients have benefited from them. The conventional treatment for TNBC remains chemotherapy. Chemoresistance, however, impedes therapeutic progress over time, and chemotherapy toxicity increases the burden of cancer on patients. Therefore, introducing more advantageous TNBC treatment options is a necessity. Metabolic reprogramming centered on glucose metabolism is considered a hallmark of tumors. It is described as tumor cells tend to convert glucose to lactate even under normoxic conditions, a phenomenon known as the Warburg effect. Similar to Darwinian evolution, its emergence is attributed to the selective pressures formed by the hypoxic microenvironment of pre-malignant lesions. Of note, the Warburg effect does not disappear with changes in the microenvironment after the formation of malignant tumor phenotypes. Instead, it forms a constitutive expression mediated by mutations or epigenetic modifications, providing a robust selective survival advantage for primary and metastatic lesions. Expanding evidence has demonstrated that the Warburg effect mediates multiple invasive behaviors in TNBC, including proliferation, metastasis, recurrence, immune escape, and multidrug resistance. Moreover, the Warburg effect-targeted therapy has been testified to be feasible in inhibiting TNBC progression. However, not all TNBCs are sensitive to glycolysis inhibitors because TNBC cells flexibly switch their metabolic patterns to cope with different survival pressures, namely metabolic plasticity. Between the Warburg effect-targeted medicines and the actual curative effect, metabolic plasticity creates a divide that must be continuously researched and bridged.

MiR-130b modulates the invasive, migratory, and metastatic behavior of leiomyosarcoma.

Leiomyosarcoma (LMS) is an aggressive, often poorly differentiated cancer of the smooth muscle (SM) lineage for which the molecular drivers of transformation and progression are poorly understood. In microRNA (miRNA) profiling studies, miR-130b was previously found to be upregulated in LMS vs. normal SM, and down-regulated during the differentiation of mesenchymal stem cells (MSCs) into SM, suggesting a role in LMS tumor progression. In the present study, the effects of miR-130b on human LMS tumorigenesis were investigated. Stable miR-130b overexpression enhanced invasion of LMS cells in vitro, and led to the formation of undifferentiated, pleomorphic tumors in vivo, with increased growth and metastatic potential compared to control LMS cells. TSC1 was identified as a direct miR-130b target in luciferase-3'UTR assays, and shRNA-mediated knockdown of TSC1 replicated miR-130b effects. Loss-of-function and gain-of-function studies showed that miR-130b levels regulate cell morphology and motility. Following miR-130b suppression, LMS cells adopted a rounded morphology, amoeboid mode of cell movement and enhanced invasive capacity that was Rho/ROCK dependent. Conversely, miR-130b-overexpressing LMS cells exhibited Rho-independent invasion, accompanied by down-regulation of Rho-pathway effectors. In mesenchymal stem cells, both miR-130b overexpression and TSC1 silencing independently impaired SM differentiation in vitro. Together, the data reveal miR-130b as a pro-oncogenic miRNA in LMS and support a miR-130b-TSC1 regulatory network that enhances tumor progression via inhibition of SM differentiation.