Different Hallmarks Of Cancer Research Articles

Abstract PO3-28-11: Potassium channel activity unveils breast cancer vulnerability

Abstract Decades of studies on ion channels have vastly demonstrated the critical functions of these proteins in many physiological and pathological conditions and have provided for an extraordinary pharmacopeia of useful compounds, often with selective actions and minimal side effects. Nevertheless, the function of ion channels in controlling cancer biology is still unknown and underexplored. Our research demonstrates that breast cancer downregulates expression of specific potassium channels (e.g., Kv11.1, KCa3.1) independently of their molecular characterization (ER+, HERB2+ and TNBC). Furthermore, breast cancer patients expressing high protein level of each of these channels presents a better overall survival when compared with patients with low expression. These data indicate that potassium channels can be prognostic factors and that high activity of these protein affects tumor growth. Therefor we wanted to understand the therapeutic benefits of pharmacological targeting specific potassium channels in breast cancer. We discovered that stimulation of the Kv11.1 with specific and selective activator molecules produced a significant growth arrest in a variety of experimental systems including in vitro, in vivo and ex vivo (e.g. Patient-derived organoids) systems. Studying the biochemical pathways that underline these events we discovered that Kv11.1 agonists affects different hallmarks of cancer including metabolism, growth and metastasis signaling without producing significant side effects. For example, use of Kv11.1 agonists produced a strong suppression of oncogene protein function including c-Myc while increasing oncosuppressors such as p21 and p16. These events associated with activation of a senescent phenotype. Furthermore, stimulation of Kv11.1 channel reversed the epithelial-to-mesenchymal transition by inhibiting the WNT signaling and reduced spreading of a TNBC by arresting the metastatic process.. Furthermore, Kv11.1 activation produced a Ca2+-dependent mitochondria damage where the antioxidant transcription factor NRF2 played a fundamental role in determining resistance to death. Therefore, we conclude that targeting the Kv11.1 potassium channel in breasts cancer can be considered a new, effective and safe targeting strategy for breast cancer. Citation Format: Saverio Gentile. Potassium channel activity unveils breast cancer vulnerability [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-28-11.

Phytochemicals from Monty’s Surprise apple are absorbed in humans, increase plasma antioxidant response, and inhibit lung and breast cancer proliferation in vitro

Apples consumption is associated with improved health and reduced risk of cancer which is attributed to its phytochemical content(1). Evidence suggests that apple phytochemicals affect different Hallmarks of cancer and reduce oxidative stress, which is involved in the pathology of cancer(2). The limiting factor to obtain these effects in the human body is apple phytochemicals’ low bioavailability. Our study is focused on a heritage apple cultivar discovered in New Zealand - Monty’s Surprise. Based on our previous liquid chromatography–mass spectrometry (LC-MS) analysis this apple contains high phytochemical (mainly flavonoids) concentrations when compared to some other commercial apple cultivars available in New Zealand. This study aims to evaluate the bioavailability of Monty’s Surprise apple phytochemicals in humans and Monty’s Surprise phytochemicals’ effects on blood total antioxidant capacity and lung, and breast cancer cell proliferation. Twelve healthy participants received either apple puree or a placebo as a control in a randomised crossover human study. Blood samples were collected after overnight fasting and at regular intervals up to eight hours post-meal consumption. The main phytochemical metabolites in the participant’s plasma were evaluated by LC-MS-MS. Plasma total antioxidant capacity was evaluated by Ferric Reducing Antioxidant Power. Based on the results from the metabolomics analysis we then created a synthetic mixture of the Monty’s Surprise apple phytochemical metabolites and evaluated their effects on cell proliferation using SYBR green assay in vitro. We were able to detect twenty-seven different phytochemical metabolites in the participant’s plasma after consumption of Monty’s Surprise apple puree. The main metabolites detected were metabolites of phenolic acids, and phase II metabolites, but also phloretin metabolites. Moreover, Monty’s Surprise apple puree consumption significantly increased (p < 0.001) plasma total antioxidant capacity 30 minutes post-meal intake (from the baseline to 170.76 µmol/L ± 34.58), when compared to the placebo consumption. In addition, Monty’s Surprise apple phytochemical metabolites inhibited lung and breast cancer cell proliferation at different concentrations. Results from this study demonstrated that Monty’s Surprise apple phenolic compounds are absorbed and enter the systemic circulation after apple puree ingestion and their absorption improves plasma antioxidant status. Moreover, Monty’s Surprise apple blood metabolites inhibit lung and breast cancer cell growth in vitro. These findings suggest that incorporating Monty’s Surprise apple into the diet may improve human health and prevent cancer development.

Regulation of mitochondrial metabolism by autophagy supports leptin-induced cell migration

Leptin is an adipokine secreted by adipose tissue, which promotes tumor progression by activating canonical signaling pathways such as MAPK/ERK. Recent studies have shown that leptin induces autophagy, and this process is involved in leptin-induced characteristics of malignancy. Autophagy is an intracellular degradation process associated with different hallmarks of cancer, such as cell survival, migration, and metabolic reprogramming. However, its relationship with metabolic reprogramming has not been clearly described. The purpose of this study was to determine the role of leptin-induced autophagy in cancer cell metabolism and its association with cellular proliferation and migration in breast cancer cells. We used ER+/PR+ and triple-negative breast cancer cell lines treated with leptin, autophagy inhibition, or mitochondrial metabolism inhibitors. Our results show that leptin induces autophagy, increases proliferation, mitochondrial ATP production and mitochondrial function in ER+/PR+ cells. Importantly, autophagy was required to maintain metabolic changes and cell proliferation driven by leptin. In triple-negative cells, leptin did not induce autophagy or cell proliferation but increased glycolytic and mitochondrial ATP production, mitochondrial function, and cell migration. In triple negative cells, autophagy was required to support metabolic changes and cell migration, and autophagy inhibition decreased cellular migration similar to mitochondrial inhibitors. In conclusion, leptin-induced autophagy supports mitochondrial metabolism in breast cancer cells as well as glycolysis in triple negative cells. Importantly, leptin-induced mitochondrial metabolism promoted cancer cell migration.

Resources for Human Health from the Plant Kingdom: The Potential Role of the Flavonoid Apigenin in Cancer Counteraction.

Apigenin is one of the most widespread flavonoids in the plant kingdom. For centuries, apigenin-containing plant preparations have been used in traditional medicines to treat diseases that have an inflammatory and/or degenerative component. In the 1980s, apigenin was proposed to interfere with the process of carcinogenesis. Since then, more and more evidence has demonstrated its anticancer efficacy, both in vitro and in vivo. Apigenin has been shown to target signaling pathways involved in the development and progression of cancer, such as PI3K/Akt/mTOR, MAPK/ERK, JAK/STAT, NF-κB, and Wnt/β-catenin pathways, and to modulate different hallmarks of cancer, such as cell proliferation, metastasis, apoptosis, invasion, and cell migration. Furthermore, apigenin modulates PD1/PD-L1 expression in cancer/T killer cells and regulates the percentage of T killer and T regulatory cells. Recently, apigenin has been studied for its synergic and additive effects when combined with chemotherapy, minimizing the side effects. Unfortunately, its low bioavailability and high permeability limit its therapeutic applications. Based on micro- and nanoformulations that enhance the physical stability and drug-loading capacity of apigenin and increase the bioavailability of apigenin, novel drug-delivery systems have been investigated to improve its solubility.

Abstract C110: miR195 - A potential therapeutic molecule for breast cancer: Present and future

Abstract Breast cancer is the leading cause of death in women worldwide (Globocan 2020). Surgery, chemotherapy as well as radiation therapy are the commonly used modes of treatment and the treatment depends on the tumor type. Patients develop resistance and demonstrate poor prognosis after prolonged treatment. Hence there’s is always a need for new diagnostics and therapeutics. miRNAs are 18-22 nucleotides small RNAs known to play a role in development and disease. Deregulation of miRNAs in diseased conditions can be harnessed as potential therapeutics by miRNA mimics or miRNA inhibition by antimiRs. Till date, several miRNA-targeted therapeutics have reached clinical development. Our laboratory has shown that miR-195 not only down regulates anti-apoptotic protein bcl-2 but also key genes of lipid metabolism (FASN, HMGCR) which are upregulated in breast cancer. The altered calcium signaling is deleterious to cells and is also known to be associated with different hallmarks of cancer. We recently observed that miR-195 perturbs calcium homeostasis in breast cancer cells by down-regulating a major calcium efflux pump present on the plasma membrane. Experimental validation has been performed in breast cancer cells and spheroids using western blotting, qRT-PCR, dual luciferase assay, calcium measurements using flow cytometry and immunofluorescence. MiR-195 alters calcium homeostasis leading to ER stress and autophagy in breast cancer. The current work describes recent advances in our understanding of miRNA-195 in breast cancer. Citation Format: Paresh Purohit, Neeru Saini. miR195 - A potential therapeutic molecule for breast cancer: Present and future [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C110.

Multi-dimensional role of gangliosides in modulating cancer hallmarks and their prospects in targeted cancer therapy

Gangliosides are glycosphingolipids with prevalence in nervous tissue and their involvement in certain neuronal diseases have been widely known. Interestingly, many recent studies highlighted their importance in the development and progression of various cancers through orchestration of multiple attributes of tumorigenesis, i.e., promoting migration, invasion, escaping the host immune system, and influencing other cancer hallmarks. Therefore, the multidimensional role of gangliosides in different cancers has established them as potential cancer targets. However, the tremendous structural complexity and functional heterogeneity are the major challenges in ganglioside research. Moreover, despite numerous immunotherapeutic attempts to target different gangliosides, it has failed to yield consistent results in clinical trials owing to their poor immunogenicity, a broad range of cross-reactivity, severe side effects, lack of uniform expression as well as heterogeneity. The recent identification of selective O-acetylated ganglioside expression in cancer tissues, but not in normal tissues, has strengthened their potential as a better and specific target for treating cancer patients. It was further supported by reduced cross-reactivity and side effects in clinical trials, although poor immunogenicity remains a major concern. Therefore, in addition to characterization and identification of the biological importance of O-acetylated gangliosides, their specific and efficient targeting in cancer through engineered antibodies is an emerging area of glycobiology research. This review highlights the modulatory effect of select gangliosides on different hallmarks of cancer and presents the overall development of ganglioside targeted immunotherapies along with recent progress. Here, we have also discussed its potential for future modifications aimed towards improvement in ganglioside-based cancer therapies.

The role of ncRNA in the co-regulation of autophagy and exosome pathways during cancer progression.

Since its discovery a few decades ago, autophagy has been recognized as a crucial signaling pathway, linked to the recycling of cellular components in nutrient stress. Autophagy is a two-way sword, playing a dual role in tumorigenesis. In this catabolic process, dysfunctional organelles, biomolecules, and misfolded proteins are sequestered in the autophagosome and sent to the lysosome for degradation. Alongside, there are cellular messengers called exosomes, which are released from cells and are known to communicate and regulate metabolism in recipient cells. Multivesicular bodies (MVB) act as the intricate link between autophagy and exosome pathways. The continuous crosstalk between the two pathways is coordinated and regulated by multiple players among which ncRNA is the emerging candidates. The exosomes carry varied cargo of which non-coding RNA exerts an immediate regulatory effect on recipient cells. ncRNA is known to exhibit dual behavior in both promoting and inhibiting tumor growth. There is increasing evidence for the involvement of ncRNAs' in the regulation of different hallmarks of cancer. Different ncRNAs are involved in the co-regulation of autophagy and exosome pathways and therefore represent a superior therapeutic approach to target cancer chemoresistance. Here, we will discuss the ncRNA involved in regulating autophagy, and exosomes pathways and its relevance in cancer therapeutics.

Interactions of circadian clock genes with the hallmarks of cancer

The molecular machinery of the circadian clock regulates the expression of many genes and processes in the organism, allowing the adaptation of cellular activities to the daily light-dark cycles. Disruption of the circadian rhythm can lead to various pathologies, including cancer. Thus, disturbance of the normal circadian clock at both genetic and environmental levels has been described as an independent risk factor for cancer. In addition, researchers have proposed that circadian genes may have a tissue-dependent and/or context-dependent role in tumorigenesis and may function both as tumor suppressors and oncogenes. Finally, circadian clock core genes may trigger or at least be involved in different hallmarks of cancer. Hence, expanding the knowledge of the molecular basis of the circadian clock would be helpful to identify new prognostic markers of tumorigenesis and potential therapeutic targets.

1,2,4-Amino-triazine derivatives as pyruvate dehydrogenase kinase inhibitors: Synthesis and pharmacological evaluation

Among the different hallmarks of cancer, deregulation of cellular metabolism turned out to be an essential mechanism in promoting cancer resistance and progression. The pyruvate dehydrogenase kinases (PDKs) are well known as key regulators in cells metabolic process and their activity was found to be overexpressed in different metabolic alerted types of cancer, including the high aggressive pancreatic ductal adenocarcinoma (PDAC). To date few PDK inhibitors have been reported, and the different molecules developed are characterized by structural chemical diversity. In an attempt to find novel classes of potential PDK inhibitors, the molecular hybridization approach, which combine two or more active scaffolds in a single structure, was employed. Herein we report the synthesis and the pharmacological evaluation of the novel hybrid molecules, characterized by the fusion of three different pharmacophoric sub-units such as 1,2,4-amino triazines, 7-azaindoles and indoles, in a single structure. The synthesized derivatives demonstrated a promising ability in hampering the enzymatic activity of PDK1 and 4, further confirmed by docking studies. Interestingly, these derivatives retained a strong antiproliferative activity against pancreatic cancer cells either in 2D and 3D models. Mechanistic studies in highly aggressive PDAC cells confirmed their ability to hamper PDK axis and to induce cancer cell death by apoptosis. Moreover, in vivo translational studies in a murine syngeneic solid tumor model confirmed the ability of the most representative compounds to target the PDK system and highlight the ability to reduce the tumor growth without inducing substantial body weight changes in the treated mice.

In-silico study of asymmetric remodeling of tumors in response to external biochemical stimuli

Among different hallmarks of cancer, understanding biomechanics of tumor growth and remodeling benefits the most from the theoretical framework of continuum mechanics. Tumor remodeling initiates when cancer cells seek new homeostasis in response to the microenvironmental stimuli. Cells within a growing tumor are capable to remodel their inter- and intra-connections and become more mobile to achieve a new homeostasis. This mobility enables the tumor to undergo large deformation. In this work, we studied the remodeling of homogeneous tumors, at their early stage of growth, in the context of continuum mechanics. We developed an evolution law for the remodeling-associated deformation which correlates the remodeling to a characteristic tensor of external stimuli. The asymmetric remodeling and the induced mechanical stresses were analyzed for different types of biochemical distributions. To experimentally investigate the model, we studied the remodeling of human glioblastoma (hGB) tumoroids in response to the gradient of nutrients. Using a tumoroid-on-a-chip platform, the degree of remodeling was estimated for the ellipsoidal tumoroids over time. It was observed that higher gradient of nutrients induces higher degree of ellipticity suggesting that the gradient of nutrient is a characteristic property of nutrient distribution that derives the remodeling. We also showed that remodeling gives rise to heterogeneity in cell distribution forming circumferentially aligned cells within the tumors. Compared to the existing studies on tumor growth, our work provides a biomechanical module that relates the remodeling to biochemical stimuli, and allows for large deformation. It also includes experimental component, a necessary but challenging step, that connects the theory and reality to evaluate the practicability of the model.

Cancer Research Trends in Traditional Korean Medical Journals since 2000 - Topic Modeling Using Latent Dirichlet Allocation and Keyword Network Analysis

Objectives: The aim of this study is to analyze cancer research trends in traditional Korean medical journals indexed in the Korea Citation Index since 2000.Methods: Cancer research papers published in traditional Korean medical journals were searched in databases from inception to October 2022. The numbers of publications by journal and by year were descriptively assessed. After natural language processing, topic modeling (based on Latent Dirichlet allocation) and keyword network analysis were conducted.Results: This research trend analysis involved 1,265 papers. Six topics were identified by topic modeling: case reports on symptom management, literature reviews, experiments on apoptosis, herbal extract treatments of breast carcinoma cell lines, anti-proliferative effects of herbal extracts, and anti-tumor effects. Keyword network analysis found that the effects of herbal medicine were assessed in clinical and experimental studies, while acupuncture was mainly mentioned in clinical reports.Conclusions: Cancer research papers in traditional Korean medical journals have contributed to evidence-based medicine. Further experimental studies are needed to elucidate the effects of on different hallmarks of cancer. Rigorous clinical studies are needed to support clinical guidelines.

Nanoparticle-Mediated Delivery of STAT3 Inhibitors in the Treatment of Lung Cancer.

Lung cancer is a common malignancy worldwide, with high morbidity and mortality. Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor that not only regulates different hallmarks of cancer, such as tumorigenesis, cell proliferation, and metastasis but also regulates the occurrence and maintenance of cancer stem cells (CSCs). Abnormal STAT3 activity has been found in a variety of cancers, including lung cancer, and its phosphorylation level is associated with a poor prognosis of lung cancer. Therefore, the STAT3 pathway may represent a promising therapeutic target for the treatment of lung cancer. To date, various types of STAT3 inhibitors, including natural compounds, small molecules, and gene-based therapies, have been developed through direct and indirect strategies, although most of them are still in the preclinical or early clinical stages. One of the main obstacles to the development of STAT3 inhibitors is the lack of an effective targeted delivery system to improve their bioavailability and tumor targetability, failing to fully demonstrate their anti-tumor effects. In this review, we will summarize the recent advances in STAT3 targeting strategies, as well as the applications of nanoparticle-mediated targeted delivery of STAT3 inhibitors in the treatment of lung cancer.

The Microbiome in PDAC—Vantage Point for Future Therapies?

Microorganisms have been increasingly implicated in the pathogenesis of malignant diseases, potentially affecting different hallmarks of cancer. Despite the fact that we have recently gained tremendous insight into the existence and interaction of the microbiome with neoplastic cells, we are only beginning to understand and exploit this knowledge for the treatment of human malignancies. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid tumor with limited therapeutic options and a poor long-term survival. Recent data have revealed fascinating insights into the role of the tumoral microbiome in PDAC, with profound implications for survival and potentially therapeutic outcomes. In this review, we outline the current scientific knowledge about the clinical and translational role of the microbiome in PDAC. We describe the microbial compositions in healthy and tumoral pancreatic tissue and point out four major aspects of the microbiome in PDAC: pathogenesis, diagnosis, treatment, and prognosis. However, caution must be drawn to inherent pitfalls in analyzing the intratumoral microbiome. Among others, contamination with environmental microbes is one of the major challenges. To this end, we discuss different decontamination approaches that are crucial for clinicians and scientists alike to foster applicability and physiological relevance in this translational field. Without a definition of an exact and reproducible intratumoral microbial composition, the exploitation of the microbiome as a diagnostic or therapeutic tool remains theoretical.

Functional role of lncRNAs in gastrointestinal malignancies: the peculiar case of small nucleolar RNA host gene family.

Long noncoding RNAs (lncRNAs) play crucial roles in normal physiology and are often de-regulated in disease states such as cancer. Recently, a class of lncRNAs referred to as the small nucleolar RNA host gene (SNHG) family have emerged as important players in tumourigenesis. Here, we discuss new findings describing the role of SNHGs in gastrointestinal tumours and summarize the three main functions by which these lncRNAs promote carcinogenesis, namely: competing with endogenous RNAs, modulating protein function, and regulating epigenetic marking. Furthermore, we discuss how SNHGs participate in different hallmarks of cancer, and how this class of lncRNAs may serve as potential biomarkers in cancer diagnosis and therapy.

Long-term exposure to nanoplastics alters molecular and functional traits related to the carcinogenic process

Micro/nanoplastics (MNPLs) are considered emergent pollutants widely spread over all environmental compartments. Although their potential biological effects are being intensively evaluated, many doubts remain about their potential health effects in humans. One of the most underdeveloped fields is the determination of the potential tumorigenic risk of MNPLs exposure. To shed light on this topic, we have designed a wide battery of different hallmarks of cancer applied to prone-to-transformed progress MEF cells exposed to polystyrene nanoplastics (PSNPLs) in the long term (6 months). Interestingly, most of the evaluated hallmarks of cancer are exacerbated after exposure, independently if they are associated with an early tumoral phenotype (changes in stress-related genes, or microRNA deregulation), advanced tumoral phenotype (growing independently of anchorage ability, and migration capacity), or an aggressive tumoral phenotype (invasion potential, changes in pluripotency markers, and ability to grow to form tumorspheres). This set of obtained data constitutes a relevant warning on the potential carcinogenic risk associated with long-term exposures to MNPLs, specifically that induced by the PSNPLs evaluated in this study.

P463: RE-PURPOSING OF GENE SIGNATURES IN AML UNCOVERS NOVEL ENERGETICS-ASSOCIATED MOLECULAR SUBTYPES

Background: AML is a highly heterogeneous disease with great diversity in clinical features and patient response to treatments. Despite recent improvements in disease understanding, treatments have remained unchanged for 30 years. This presents the need to characterise the disease more fully and characterise its underpinning molecular subtypes. The re-use of published and validated prognostic and predictive gene signatures e.g. Cancer Hallmarks presents an invaluable in silico opportunity to uncover the biological mechanisms underpinning treatment response in AML. Aims: To develop an automated statistical analysis pipeline combined with machine learning techniques to derive robust patient clusters representative of novel molecular AML subtypes significantly associated with clinical variables and survival outcomes. Methods: Analysis was carried out using a primary dataset (AML-OHSU: 451 AML patient samples) and a validation dataset (TCGA-LAML: 200 AML patient samples). Both datasets had been processed using Almac’s claraT platform, a software-driven solution which provides a comprehensive overview of tumour profiles using gene expression signatures. An automated analytical pipeline was developed using Consensus Clustering (CC), a method that determines the number and membership of potential clusters, using different combinations of 8 distances and 7 linkages within a dataset. Robustness was tested via bootstrapping. This pipeline was used to stratify patients via a dimension reduction approach whereby clustering was performed on 210 gene signatures categorised by 10 different hallmarks of cancer. Analysis was performed to identify clinical associations within robust clusters that were linked to differences in survival. Results: The automated clustering pipeline analysed a total of 1,314 stable clusters across 10 cancer hallmarks in the AML-OHSU dataset. Stable clusters were subsequently processed via log rank analysis (OS right-censored at 60 months) identifying 134 stable clusters with significant differences (p-value <0.05) in survival outcome. Stable clusters with significant survival differences were tested against 32 clinical categorical variables present in the AML-OHSU dataset. The results were filtered for a significant threshold (chi square p-value <0.05 and BH p-value <0.2). Here we found gene signatures representative of the Energetics hallmark, incorporating 22 signatures, to be one of the most frequently clustered throughout our results, ranking highest where K=3. A significant difference in overall survival probability (Log rank p-value: 0.033) was found between clusters (Energetics, K=3). Patients in the poorest survival cluster were characterised by a refectory induction response to treatment, having the lowest number of fusions, a low frequency of NPM1 mutations and a high proportion of patients above the age of 65. To validate energetics results from the AML-OHSU dataset, CC was again performed using gene signatures from the TCGA dataset that were representative of the energetics hallmark. A significant difference between overall survival probability (Log rank p-value: 0.019) was again found between stable clusters of the energetics hallmark (K = 3). Summary/Conclusion: We have demonstrated that a novel analytical pipeline developed here to analyse Hallmark-related gene signatures can aid in the discovery of new molecular subtypes in AML associated with prognosis. We have subsequently validated these in an independent dataset. The Energetics hallmark has not, to our knowledge, been linked with AML prognosis before, and may suggest novel biology linked to treatment response.

G Protein-Coupled Receptors: Undervalued Targets for Cancer Therapy

Despite the G protein-coupled receptors (GPCRs) being the largest family of signalling proteins at the surface of cells, their potential to be targeted in cancer therapy is still under-utilised. This review highlights the contribution of these receptors to the process of oncogenesis and points to some likely challenges that might be encountered in targeting them. GPCR-signalling pathways are often complex and can be tissue-specific. Cancer cells hijack these communication networks to their proliferative advantage. The role of selected GPCRs in the different hallmarks of cancer is examined to highlight the complexity of targeting these receptors for therapeutic benefit. Our increasing knowledge of the mechanisms governing the molecular functions of GPCRs may help to identify new targets to treat specific types of cancers.

Identification of novel key regulatory lncRNAs in gastric adenocarcinoma

BackgroundStomach adenocarcinoma (STAD) is one of the most common and deadly cancers worldwide. Recent evidence has demonstrated that dysregulation of long noncoding RNAs (lncRNA) is associated with different hallmarks of cancer. lncRNAs also were suggested as novel promising biomarkers for cancer diagnosis and prognosis. Despite these previous investigations, the expression pattern, diagnostic role, and hallmark association of lncRNAs in STAD remain unclear.ResultsIn this study, The STAD lncRNA-mRNA network was constructed based on RNAs that differentially expressed among tumor and normal samples and had a strong expression correlation with others. The high degree nodes of the network were associated with overall survival. In addition, we found that the hubs’ regulatory roles have previously been confirmed in different types of cancers by literature. For example, the HCG22 hub inhibited cell proliferation and invasion and induced apoptosis in oral squamous cell carcinoma (OSCC) cells. The levels of PCNA, Vimentin, and Bcl2 were decreased and E-cadherin and Bax expression was elevated in OSCC cells after HCG22 overexpression. Additionally, HCG22 overexpression inhibited the Akt, mTOR, and Wnt/β-catenin pathways.Then lncRNAs were mapped to their related GO terms and cancer hallmarks. Based on these mappings, we predict the hallmarks that might be associated with each lncRNA. Finally, the literature review confirmed our prediction.Among the 20 lncRNAs of the STAD network, 11 lncRNAs (LINC02560, SOX21-AS1, C5orf66-AS1, HCG22, PGM5-AS1, NALT1, ENSG00000241224.2, TINCR, MIR205HG, HNF4A-AS1, ENSG00000262756) demonstrated expression correlation with overall survival (OS). Based on expression analysis, survival analysis, hallmark associations, and literature review, LINC02560, SOX21-AS1, C5orf66-AS1, HCG22, PGM5-AS1, NALT1, ENSG00000241224.2, TINCR, MIR205HG, HNF4A-AS1 plays a regulatory role in STAD. For example, our prediction of association between C5orf66-AS1 expression dysregulation and “sustaining proliferative signal” and “Activating invasion and metastasis” has been confirmed in STAD, OSCC and cervical cancer. Finally, we developed a lncRNA signature with SOX21-AS1 and LINC02560, which classified patients into high and low-risk subgroups with significantly different survival outcomes. The mortality rate of the high-risk patients was significantly higher compared to the low-risk patients (28/1% vs 60.13).ConclusionThese findings help in designing more precise and detailed experimental studies to find STAD biomarkers and therapeutic targets.

Pioneer Role of Extracellular Vesicles as Modulators of Cancer Initiation in Progression, Drug Therapy, and Vaccine Prospects.

Cancer is one of the leading diseases, causing deaths worldwide. Nearly 10 million deaths were reported in 2020 due to cancer alone. Several factors are involved in cancer progressions, such as lifestyle and genetic characteristics. According to a recent report, extracellular vesicles (EVs) are involved in cancer initiation, progression, and therapy failure. EVs can play a major role in intracellular communication, the maintenance of tissue homeostasis, and pathogenesis in several types of diseases. In a healthy person, EVs carry different cargoes, such as miRNA, lncRNA etc., to help other body functions. On the other hand, the same EV in a tumor microenvironment carries cargoes such as miRNA, lncRNA, etc., to initiate or help cancer progression at various stages. These stages may include the proliferation of cells and escape from apoptosis, angiogenesis, cell invasion, and metastasis, reprogramming energy metabolism, evasion of the immune response, and transfer of mutations. Tumor-derived EVs manipulate by altering normal functions of the body and affect the epigenetics of normal cells by limiting the genetic makeup through transferring mutations, histone modifications, etc. Tumor-derived EVs also pose therapy resistance through transferring drug efflux pumps and posing multiple drug resistances. Such EVs can also help as biomarkers for different cancer types and stages, which ultimately help with cancer diagnosis at early stages. In this review, we will shed light on EVs’ role in performing normal functions of the body and their position in different hallmarks of cancer, in altering the genetics of a normal cell in a tumor microenvironment, and their role in therapy resistance, as well as the importance of EVs as diagnostic tools.

3197 – RE-PURPOSING OF GENE SIGNATURES IN AML UNCOVERS NOVEL MOLECULAR SUBTYPES ASSOCIATED WITH ENERGETICS

AML is a highly heterogeneous disease with great diversity in patient treatment response. This presents the need to better characterise the disease and its underpinning molecular subtypes. The re-use of published and validated prognostic predictive gene signatures present an invaluable in silico opportunity to uncover the biological mechanisms underpinning treatment response in AML. Analysis was carried out using a primary dataset (AML-OHSU) and a validation dataset (TCGA-LAML: 200 AML patient samples). Both datasets had been processed using Almac's claraT platform, a software solution which provides a comprehensive overview of tumour profiles via gene expression signatures. An automated analytical pipeline was developed using Consensus Clustering, a method that determines the number and membership of patient clusters within a dataset. Robustness was tested via bootstrapping. This pipeline was used to stratify patients using 451 gene signatures categorised by 10 different hallmarks of cancer. The automated clustering pipeline analysed a total of 1,314 stable clusters in the AML-OHSU dataset. Stable clusters were subsequently processed via log rank analysis identifying 134 stable clusters with significant differences (p-value < 0.05) in survival outcome. Here we found gene signatures representative of the Energetics hallmark to be one of the most frequently clustered throughout our results, ranking highest where K=3. A significant difference in overall survival probability (Log rank p-value: 0.033) was found between clusters. To validate energetics results from the AML-OHSU dataset, consensus clustering was again performed using gene signatures from the TCGA dataset that were representative of the energetics hallmark. A significant difference between overall survival probability (Log rank test p-value: 0.019) was again found between stable clusters AML is a highly heterogeneous disease with great diversity in patient treatment response. This presents the need to better characterise the disease and its underpinning molecular subtypes. The re-use of published and validated prognostic predictive gene signatures present an invaluable in silico opportunity to uncover the biological mechanisms underpinning treatment response in AML. Analysis was carried out using a primary dataset (AML-OHSU) and a validation dataset (TCGA-LAML: 200 AML patient samples). Both datasets had been processed using Almac's claraT platform, a software solution which provides a comprehensive overview of tumour profiles via gene expression signatures. An automated analytical pipeline was developed using Consensus Clustering, a method that determines the number and membership of patient clusters within a dataset. Robustness was tested via bootstrapping. This pipeline was used to stratify patients using 451 gene signatures categorised by 10 different hallmarks of cancer. The automated clustering pipeline analysed a total of 1,314 stable clusters in the AML-OHSU dataset. Stable clusters were subsequently processed via log rank analysis identifying 134 stable clusters with significant differences (p-value < 0.05) in survival outcome. Here we found gene signatures representative of the Energetics hallmark to be one of the most frequently clustered throughout our results, ranking highest where K=3. A significant difference in overall survival probability (Log rank p-value: 0.033) was found between clusters. To validate energetics results from the AML-OHSU dataset, consensus clustering was again performed using gene signatures from the TCGA dataset that were representative of the energetics hallmark. A significant difference between overall survival probability (Log rank test p-value: 0.019) was again found between stable clusters