Oncogenic Processes Research Articles

Abstract 6238: Integrated multi-omic/modal profiling enables improved characterization of oncogenic processes, with impact to clinical actionability in the GenMineTOP tested population

Abstract Introduction: It is becoming increasingly apparent that tumor gene expression and spatial H&E profiling can be used to improve the accuracy of DNA-only tumor profiling for clinically relevant use-cases. Future development and deployment of integrative (multi-omic (DNA+RNA) and/or multi-modality (omics + imaging)) tests for treatment and clinical trial profiling hinges on the demonstration of clear robustness and performance gains of prognostic and predictive integrative predictors in a clinical setting. In this work we present several analyses quantifying the utility of integrative testing. We show that a multi-omic test combining tumor expression signatures with DNA profiles substantially improves tumor-of-origin prediction for cancers of unknown primary and also significantly improves MSI detection and resolution. We also show that a simple multi-modality model combining spatial features of tumor infiltrating lymphocytes of tumors with tumor expression is prognostic for MSI-positive patients. Methods: Multi-omicTumor-of-origin: 163 patient sample expression profiles were profiled using the GenMineTOP test. GenMineTOP is a tumor-normal, joint DNA+RNA capture PMDA-approved test in current clinical service in Japan. The samples were clustered using DNA-only, RNA-only, and joint DNA+RNA profiling signatures. MSI prediction: 940 samples from the TCGA COAD, UCEC, and READ cohorts with matched MMR IHC MSI-calling, DNA-NGS-based MSI calling, and RNA-seq data were utilized to train, test and validate an expression-based pan-cancer MSI caller. Additional orthogonal validation was carried out using GenMineTOP multi-omic profiles. Multi-modality Spatial context of TIL and tumor-expression: 158 MSI+ samples from the TCGA-UCEC cohort with matched fresh-frozen H&E 20X images and RNA-seq data were utilized to mine spatial features of tumor-infiltrating lymphocytes and derive gene expression signatures, respectively. A Cox-proportional hazard model for patient survival using gene expression and spatial TIL features was constructed while regressing out tumor stage, gender, age, and ethnicity. Results & Conclusions: Our multi-omic results quantify the benefit of combining DNA and RNA profiles from GenMineTOP to classify tumor-of-origin from unknown primaries reduces classification error by approximately 50%. Additionally, our expression-based MSI status prediction model not only significantly improves NGS DNA (MSI-sensor) based MSI prediction (log-ratio test, pval < 1e-7) but also strongly suggests that nonlinear differential expression drives the improvement in MSI prediction. Our multi-modality results demonstrate that mining the spatial context of endogenous tumor immune response has nontrivial prognostic utility (p < .05). Citation Format: Bojan Losic, Kenji Tatsuno, Vasanth R. Singan, Hiroki Ueda, Aya Shinozaki Ushiku, Vasanthan Jayakumar, Emi Hattori, Toshimitsu Ichijo, Takuma Sasa, Masakazu Akahori, Shinya Hayashi, Esther Hsiao, Stephanie Feupe, Dan Vo, Tiantian Geier, Shuichi Tsutsumi, Tetsuo Ushiku, Kousuke Watanabe, Katsutoshi Oda, Hidenori Kage, Joy Radecki-Crandall, Donavan T. Cheng, Hiroyuki Aburatani. Integrated multi-omic/modal profiling enables improved characterization of oncogenic processes, with impact to clinical actionability in the GenMineTOP tested population [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 6238.

Identification of CREB5 as a prognostic and immunotherapeutic biomarker in glioma through multi-omics pan-cancer analysis

BackgroundThe functional relevance of cyclic adenosine monophosphate (cAMP)-response element-binding protein 5 (CREB5) in cancers remains elusive, despite its significance as a member of the CREB family. The current research aims to explore the role of CREB5 in multiple cancers. MethodsPan-cancer analysis was performed to explore the expression patterns, prognostic value, mutational landscape as well as single-cell omic, immunologic, and drug sensitivity profiles of CREB5. Furthermore, we incorporated five distinct machine learning algorithms and determined that the least absolute shrinkage and selection operator-COX (LASSO-COX) algorithm, which exhibited the highest C index, was the optimal selection. Subsequently, we constructed a prognostic model centered around CREB5-associated genes. To elucidate the biological function of CREB5 in glioma cells, several assays including cell counting kit-8 (CCK-8), wound healing, transwell, flow cytometric were performed. ResultsCREB5 was overexpressed in pan-cancer and was linked to unfavorable prognosis, particularly in glioma. Furthermore, genetic alterations were determined in various types of cancer, and modifications in the CREB5 gene were linked to the prognosis. The single-cell omics and enrichment analyses showed that CREB5 was predominantly expressed in malignant glioma cells and was critically involved in the regulation of various oncogenic processes. Elevated levels of CREB5 were strongly linked with the infiltration of cancer-associated fibroblasts and the Th1 subset of CD4+ T cells. The validated CREB5-associated prognostic model reliably predicted the prognosis and drug response of glioma patients. The in vitro experiments showed that CREB5 promoted glioma cell proliferation, invasion, migration, and gap phase 2/mitotic (G2/M) phase arrest and recruited M2 macrophages into glioma cells. ConclusionCREB5 has the potential to act as an oncogene and a biological marker in multiple cancers, particularly glioma.

O148: Unlocking Enhanced Immunity in Pancreatic Ductal Adenocarcinoma: Activins Interplay with CAF-Stroma Mechanisms

Abstract SMAD4 is a tumour suppressor gene that is mutated in up to 60% of pancreatic ductal adenocarcinoma (PDAC) tumours. Activins are members of the TGF-b signalling superfamily which signal through SMAD4 and are generally associated with an oncogenic process, with differing effects on tumour and stromal cells, such as cancer associated fibroblasts (CAFs). We sought to further elucidate the role of activin within PDAC and perturb activin signalling in vitro and in vivo. Analysis was performed of publicly available human datasets alongside human and murine single-cell RNA-sequencing datasets to study the effect of activin expression on survival and tumourigenesis. We developed anti-activin monoclonal antibodies to perturb activin signalling in PDAC mice, with deep analysis of tumour composition including immune cells and CAFs via a multitude of basic science techniques. We demonstrated that circulating activin levels are higher in PDAC patients than in healthy volunteers, whilst activin overexpression is associated with reduced overall survival in PDAC patients. Activin was shown to be predominantly expressed by contractile (collagen-depositing) CAFs, as opposed to inflammatory CAFs. Activin expression co-localises with fibroblasts, and anti-activin antibodies can reduce the collagen content of dense PDAC tumours. Additionally, anti-activin antibodies led to a statistically significant increase in CD4 and CD8 T-cell infiltration into murine PDAC tumours. We have shown that activin is overexpressed in PDAC, and high expression is associated with a more aggressive disease process. Anti-activin antibodies can alter the composition of desmoplastic PDAC tumours and increase the immune infiltrate of these typically “immune cold” tumours.

In silico investigation of the role of miRNAs in a possible developmental origin of prostate cancer in F1 and F2 offspring of mothers exposed to a phthalate mixture.

A previous study using miRNA sequencing revealed that exposure to a mixture of phthalates during pregnancy and lactation dysregulated rno-miR-184 and rno-miR-141-3p in the ventral prostate (VP) of offspring. Here, rno-miR-184 and rno-miR-141-3 expressions were obtained by RT-qPCR in the VP of F1 males as well as in F2 offspring, aiming to establish a relationship with possible oncogenic targets through in silico analyses with multigenerational approach. Additionally, some targets were measured by western blots to highlight a possible relationship between the deregulated miRNAs and some of their targets. VP samples from rats exposed to a mixture of phthalates maternally during pregnancy and lactation (GD10 to PND21-F1) and VP from offspring (F2) were examined. The phthalate mixture at both concentrations (20 μg and 200 mg/kg/day) increased the expression of both miRNAs in the F1 (PND22 and 120) and F2 (descendants of F1-treated males) prostate. Target prediction analysis revealed that both microRNAs are responsible for modulating the expression and synthesis of 40 common targets. A phthalate target association analysis and the HPA database showed an interesting relationship among these possible miRNAs modulated targets with prostate adenocarcinoma and other oncogenic processes. Western blots showed alteration in P63, P53, WNT5, and STAT3 expression, which are targeted by the miRNAs, in the VP of F1/F2 males. The data draw attention to the epigenetic modulation in the prostate of descendants exposed to phthalates and adds to one of the few currently found in the literature to point to microRNAs signature as biomarkers of exposure to plasticizers.

A Cyclic Permutation Approach to Removing Spatial Dependency between Clustered Gene Ontology Terms.

Traditional gene set enrichment analysis falters when applied to large genomic domains, where neighboring genes often share functions. This spatial dependency creates misleading enrichments, mistaking mere physical proximity for genuine biological connections. Here we present Spatial Adjusted Gene Ontology (SAGO), a novel cyclic permutation-based approach, to tackle this challenge. SAGO separates enrichments due to spatial proximity from genuine biological links by incorporating the genes' spatial arrangement into the analysis. We applied SAGO to various datasets in which the identified genomic intervals are large, including replication timing domains, large H3K9me3 and H3K27me3 domains, HiC compartments and lamina-associated domains (LADs). Intriguingly, applying SAGO to prostate cancer samples with large copy number alteration (CNA) domains eliminated most of the enriched GO terms, thus helping to accurately identify biologically relevant gene sets linked to oncogenic processes, free from spatial bias.

Abstract B095: Tenascin C promotes ovarian cancer stem cells interactions with the niche

Abstract Background: Effective treatment of ovarian cancer (OC) is greatly impacted by advanced, late-stage diagnosis which usually presents with intra-peritoneal metastases, chemoresistance and high recurrence. The development of intra-peritoneal metastases is correlated with the formation of multicellular spheroids disseminated in the peritoneal fluid. Spheroid formation is promoted by a change of cell adhesion properties, enhanced secretion of extracellular matrix (ECM) components that stiffen the tumor stroma and promote the aberrant activation of oncogenic processes, including survival, invasion, and stemness. Tenascin C (TNC) is one of the molecules secreted in the ECM and correlates with migration and metastatic progression in a variety of carcinomas. However, the functional role of TNC in spheroid formation and in the maintenance of the platinum resistant ovarian cancer stem phenotype has not been investigated yet. We tested the hypothesis that the increased expression of TNC and its secretion in the ECM compartment promotes survival of OCSCs, supports OC spheroid formation and tumor progression. Methods: We compared TNC expression in OC cells grown as spheroids and monolayers and in chemoresistant vs sensitive OC cells by realtime-PCR and Western Blot (WB). TNC blockade by siRNA knockdown (KD) was evaluated in combination with carboplatin on spheroid assay, colony formation, and by qPCR of stemness related gene expression. Chromatin immunoprecipitation (ChIP) assay detected the interaction between the β-catenin and the TNC promoter. Results: OC cells grown as spheroids showed a significant increase in TNC expression compared to monolayers. Our results also demonstrated an increase in TNC expression levels in platinum resistant OC cell lines when compared to the platinum sensitive counterpart. A comparison of normal adjacent ovarian epithelium and primary OC tumors on a multitissue array revealed that TNC expression coincided with a pro-tumorigenic phenotype (n=88, P<0.001), correlating with poor outcome. TNC-KD in combination with carboplatin led to a significant decrease in the expression levels of stemness-related genes, spheroid and colony formation. Mechanistically, b-catenin-KD decreased TNC expression levels and β-catenin coimmunoprecipitated with the TNC promoter, suggesting that TNC is a direct β-catenin target. Additionally, OC spheroids treated with the Wnt ligand WNT-3A showed increased TNC expression compared to control untreated cells, as demonstrated by WB. Importantly, the enhanced expression of TNC was followed by its secretion in the ECM compartment, as observed via immunofluorescence imaging, implying a direct role of TNC in the ECM-rearrangement which is responsible for CSC maintenance and spheroid formation. Conclusions: TNC is strongly linked to chemoresistance and is regulated by the oncogenic β-catenin pathway. Our data suggest that strategies aimed at interfering with TNC expression and/or secretion along with carboplatin treatment could be a potential combination therapy in OC. Citation Format: Amber Rogers, Maya Shebeshi, Morganna Gordon, Rula Atwani, Virginie Lazar, Salvatore Condello. Tenascin C promotes ovarian cancer stem cells interactions with the niche [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B095.

The intersection of heart failure and cancer in women: a review.

Cancer and cardiovascular disease represent the two leading causes of morbidity and mortality worldwide. Women continue to enjoy a greater life expectancy than men. However, this comes at a cost with more women developing diabetes, hypertension and coronary artery disease as they age. These traditional cardiovascular risk factors not only increase their lifetime risk of heart failure but also their overall risk of cancer. In addition to this, many of the cancers with female preponderance are treated with potentially cardiotoxic therapies, adding to their increased risk of developing heart failure. As a result, we are faced with a higher risk population, potentially suffering from both cancer and heart failure simultaneously. This is of particular concern given the coexistence of heart failure and cancer can confer a worse prognosis than either a single diagnosis of heart failure or cancer alone. This review article explores the intersection of heart failure and cancer in women at multiple levels, including traditional cardiovascular risk factors, cardiovascular toxicity derived from antineoplastic and radiation therapy, shared pathophysiology and HF as an oncogenic process. This article further identifies opportunities and strategies for intervention and optimisation, whilst highlighting the need for contemporary guidelines to better inform clinical practice.

Mechanistic Investigation of Thiazole-Based Pyruvate Kinase M2 Inhibitor Causing Tumor Regression in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a deadly breast cancer with a poor prognosis. Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme in glycolysis, is abnormally highly expressed in TNBC. Overexpressed PKM2 amplifies glucose uptake, enhances lactate production, and suppresses autophagy, thereby expediting the progression of oncogenic processes. A high mortality rate demands novel chemotherapeutic regimens at once. Herein, we report the rational development of an imidazopyridine-based thiazole derivative 7d as an anticancer agent inhibiting PKM2. Nanomolar range PKM2 inhibitors with favorable drug-like properties emerged through enzyme assays. Experiments on two-dimensional (2D)/three-dimensional (3D) cell cultures, lactate release assay, surface plasmon resonance (SPR), and quantitative real-time polymerase chain reaction (qRT-PCR) validated 7d preclinically. In vivo, 7d outperformed lapatinib in tumor regression. This investigation introduces a lead-based approach characterized by its clear-cut chemistry and robust efficacy in designing an exceptionally potent inhibitor targeting PKM2, with a focus on combating TNBC.

MicroRNA-302a enhances 5-fluorouracil sensitivity in HepG2 cells by increasing AKT/ULK1-dependent autophagy-mediated apoptosis

Abstract Objectives MicroRNA-302a (miR-302a) has been implicated in the oncogenic processes, but its role in hepatocellular carcinoma (HCC) chemoresistance and related mechanisms are still unclear. Therefore, the aim of this study was to investigate the role of miR-302a in HCC chemoresistance and elucidate its underlying mechanism. Methods In this study, we detected the level of miR-302a in HCC tissues (including chemoresistant and chemosensitive tissues), non-tumor tissues, liver cancer cell lines, and 5-fluorouracil (5-FU)-resistant cells (HepG2/R). Additionally, we conducted cell viability, apoptosis, and autophagy analyses as well as assessed the levels of cleaved caspase-3, cleaved caspase-9, microtubule-associated protein 1 light chain 3 beta II (LC3B-II), Akt, and UNC-51 like kinase 1 (ULK1) in HepG2 cells transfected with miR-302a mimic or inhibitor prior to 5-FU treatment. Lastly, we predicted the target of miR-302a and verified the relationship between miR-302a and Akt by luciferase reporter and functional repair assays. Results Our results revealed that miR-302a was down-regulated in HCC tissues (p<0.01), especially in chemoresistant tissues (p<0.01). Consistently, the miR-302a level exhibited a lower expression in HepG2/R cells compared to their parental cells (p<0.01). Furthermore, the 5-FU-induced apoptosis and autophagy of HepG2 cells were promoted by miR-302a over-expression and diminished by miR-302a inhibition (p<0.01). Target analysis revealed that miR-302a could directly target Akt. Moreover, miR-302a inhibited Akt expression and subsequently elevated ULK1 expression (p<0.01). Inhibition of ULK1 could abrogate the sensitization of overexpressed miR-302a to 5-FU in HepG2 cells (p<0.01). Conclusions Altogether, our results demonstrate that the down-regulation of miR-302a promotes 5-FU resistance in HCC by attenuating the Akt/ULK1 axis-dependent autophagy and apoptosis.

Closed‐loop of Catalyzed Lactate Oxidization Synergistically Sensitizes Apoptosis and Ferroptosis for Cancer Therapy

AbstractLactate accumulated in Tumor is a key oncometabolite and associated with various oncogenic processes, including proliferation, invasion, angiogenesis, metastasis, immunosuppression and therapeutic resistance. Particularly, lactate contributes to the apoptosis and ferroptosis resistance in cancer cells. Consequently, blockade of lactate provides a promising opportunity for cancer therapy. However, due to abnormal tumor microenvironment (TME) and intracellular glutathione (GSH) mediated ferroptosis resistance, the current approaches for regulating lactate to sensitize cells to apoptosis and ferroptosis are still challenging. Herein, we developed a catalytic lactate oxidizing liposomes (Lip‐LM) incorporated with lactate oxidase (LOX)‐loaded MnO2 nanoparticles. O2 regenerated from H2O2 constitute closed‐loop of lactate oxidation catalyzed by LOX, enhancing the lactate‐consuming efficacy in TME. Besides, glutathione is consumed by MnO2 to amplify the ferroptosis susceptibility of cancer cells. The results showed that Lip‐LM achieved synergistical apoptosis and ferroptosis to enhance the anti‐tumor efficacy of amplified oxidative stress in cancer cells through the strategy of self‐sufficient O2 supplying and GSH consumption. The results of transcriptomics and proteomics analyses also support the synergistical anti‐tumor mechanisms of Lip‐LM. Hence, it is a promising catalytic nanoplatform combined lactate regulation and oxidative stress amplification and have great potential to further enhance therapeutic outcomes based on synergistical apoptosis and ferroptosis.

New analysis of atypical spermatocytic tumours reveals extensive heterogeneity and plasticity of germ cell tumours†.

Testicular germ cell tumours (TGCTs) derived from immature (type I) and pluripotent germ cell neoplasia in situ (GCNIS, type II) are characterised by remarkable phenotypic heterogeneity and plasticity. In contrast, the rare spermatocytic tumour (SpT, type III), derived from mature spermatogonia, is considered a homogenous and benign tumour but may occasionally present as an anaplastic or an aggressive sarcomatoid tumour. While various oncogenic processes had been proposed, the precise mechanism driving malignant progression remained elusive until the molecular characterisation of a series of atypical SpTs described in a recent issue of The Journal of Pathology. The emerging picture suggests the presence of two distinct trajectories for SpTs, involving either RAS/mitogen-activated protein kinase pathway mutations or a ploidy shift with secondary TP53 mutations and/or gain of chromosome 12p, the latter known as pathognomonic for type II GCNIS-derived TGCTs. Here, we discuss the implications of these findings, seen from the perspective of germ cell biology and the unique features of different TGCTs. The evolving phenotype of SpTs, induced by genomic and epigenetic changes, illustrates that the concept of plasticity applies to all germ cell tumours, making them inherently heterogenous and capable of significant transformation during progression. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Epigenetic regulation in cancer.

Epigenetic modifications are defined as heritable changes in gene activity that do not involve changes in the underlying DNA sequence. The oncogenic process is driven by the accumulation of alterations that impact genome's structure and function. Genetic mutations, which directly disrupt the DNA sequence, are complemented by epigenetic modifications that modulate gene expression, thereby facilitating the acquisition of malignant characteristics. Principals among these epigenetic changes are shifts in DNA methylation and histone mark patterns, which promote tumor development and metastasis. Notably, the reversible nature of epigenetic alterations, as opposed to the permanence of genetic changes, positions the epigenetic machinery as a prime target in the discovery of novel therapeutics. Our review delves into the complexities of epigenetic regulation, exploring its profound effects on tumor initiation, metastatic behavior, metabolic pathways, and the tumor microenvironment. We place a particular emphasis on the dysregulation at each level of epigenetic modulation, including but not limited to, the aberrations in enzymes responsible for DNA methylation and histone modification, subunit loss or fusions in chromatin remodeling complexes, and the disturbances in higher-order chromatin structure. Finally, we also evaluate therapeutic approaches that leverage the growing understanding of chromatin dysregulation, offering new avenues for cancer treatment.

Dysregulation of RNA splicing in early non-alcoholic fatty liver disease through hepatocellular carcinoma

While changes in RNA splicing have been extensively studied in hepatocellular carcinoma (HCC), no studies have systematically investigated changes in RNA splicing during earlier liver disease. Mouse studies have shown that disruption of RNA splicing can trigger liver disease and we have shown that the splicing factor SRSF3 is decreased in the diseased human liver, so we profiled RNA splicing in liver samples from twenty-nine individuals with no-history of liver disease or varying degrees of non-alcoholic fatty liver disease (NAFLD). We compared our results with three publicly available transcriptome datasets that we re-analyzed for splicing events (SEs). We found many changes in SEs occurred during early liver disease, with fewer events occurring with the onset of inflammation and fibrosis. Many of these early SEs were enriched for SRSF3-dependent events and were associated with SRSF3 binding sites. Mapping the early and late changes to gene ontologies and pathways showed that the genes harboring these early SEs were involved in normal liver metabolism, whereas those harboring late SEs were involved in inflammation, fibrosis and proliferation. We compared the SEs with HCC data from the TCGA and observed that many of these early disease SEs are found in HCC samples and, furthermore, are correlated with disease survival. Changes in splicing factor expression are also observed, which may be associated with distinct subsets of the SEs. The maintenance of these SEs through the multi-year oncogenic process suggests that they may be causative. Understanding the role of these splice variants in metabolic liver disease progression may shed light on the triggers of liver disease progression and the pathogenesis of HCC.

Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling.

Ras homolog enriched in brain (Rheb1 and Rheb2), small GTPases, play a crucial role in regulating neuronal activity and have gained attention for their implications in cancer development, particularly in breast cancer. This study delves into the intricate connection between the multifaceted functions of Rheb1 in neurons and cancer, with a specific focus on the mTOR pathway. It aims to elucidate Rheb1's involvement in pivotal cellular processes such as proliferation, apoptosis resistance, migration, invasion, metastasis, and inflammatory responses while acknowledging that Rheb2 has not been extensively studied. Despite the recognized associations, a comprehensive understanding of the intricate interplay between Rheb1 and Rheb2 and their roles in both nerve and cancer remains elusive. This review consolidates current knowledge regarding the impact of Rheb1 on cancer hallmarks and explores the potential of Rheb1 as a therapeutic target in cancer treatment. It emphasizes the necessity for a deeper comprehension of the molecular mechanisms underlying Rheb1-mediated oncogenic processes, underscoring the existing gaps in our understanding. Additionally, the review highlights the exploration of Rheb1 inhibitors as a promising avenue for cancer therapy. By shedding light on the complicated roles between Rheb1/Rheb2 and cancer, this study provides valuable insights to the scientific community. These insights are instrumental in guiding the identification of novel targets and advancing the development of effective therapeutic strategies for treating cancer.

SLMO2 is a potential prognostic and immunological biomarker in human pan-cancer

SLMO2 is a lipid transporter that transports phosphatidylserine to the interior of mitochondria, also known as PRELID3B, which plays an important role in lipid metabolism. It has also been reported to be involved in the growth process of breast and lung tumors. However, its functions and underlying mechanisms in cancer progress remain elusive, and the potential as pan-cancer biomarker and therapeutic target remains unexplored. Using the TCGA project and GEO database, we performed pan-cancer analysis of SLMO2, which including the expression pattern, prognostic value, mutation landscape, methylation modification, protein–protein interaction network and the relationship between SLMO2 expression and immune infiltration. KEGG enrichment analysis was also performed to predict function and relevant cellular pathways of SLMO2. In addition, proliferation and migration assays were performed to detect the proliferation and metastasis capacity of breast cancer and lung cancer cells. In our study, we found that SLMO2 was overexpressed in pan-cancer and the elevated expression of SLMO2 was correlated with poorer prognosis. SLMO2 mutations were distributed in a variety of tumors and correlated with prognosis. Promoter methylation analysis showed that SLMO2 methylation levels were lower in most tumors compared with normal tissues, while a few tumors showed increased methylation levels of SLMO2. SLMO2 expression was also positively correlated with immune infiltration of MDSCs. Further pathway enrichment analysis indicated that SLMO2 was involved in regulating of cytoplasmic transport and other oncogenic processes. In vitro experiments have shown that SLMO2 promotes the proliferation and migration of breast cancer and lung cancer cells. In conclusion, our findings suggested that SLMO2 was a potential prognostic and immunological marker in pan-cancer. This study suggested a potential strategy for targeting SLMO2 to treat tumors, including manipulating tumor growth or the tumor microenvironment, especially the infiltration of MDSC.

Pan-cancer Multi-omics Analysis Reveals HMGN1 as a Potential Prognostic and Immune Infiltration-associated Biomarker.

The High Mobility Group Nucleosomal Binding Domain 1 Gene (HMGN1) is crucial for epigenetic regulation. However, the specific function of HMGN1 in cancer development is unclear. Raw data on HMGN1 expression were procured from Genotype-Tissue Expression (GTEx), the University of Alabama- Birmingham CANcer data analysis Portal (UALCAN), and The Cancer Genome Atlas (TCGA). Thereafter, the pan-cancer analysis was implemented to understand the HMGN1 expression patterns, prognostic value, and immunological features. Furthermore, the Gene Set Enrichment Analysis (GSEA) was executed via R language. In addition, the relationship between HMGN1 and the sensitivity of antitumor drugs was also determined. Finally, real-time PCR (RT-PCR) experiments were carried out. Pan-cancer analysis revealed that HMGN1 was upregulated in several solid tumors and was associated with pathological staging and poor prognosis. In addition, HMGN1 was found to be involved in regulating the tumor microenvironment. The GSEA enrichment analysis indicated that HMGN1 assisted in the regulation of oncogenic processes, especially metabolic and immune pathways. Furthermore, HMGN1 expression was linked to microsatellite instability (MSI) and tumor mutational burden (TMB) across diverse tumor types. RT-PCR assays indicated that HMGN1 was overexpressed in the gastric and breast cancer cell lines and tissues. This study highlighted the potential of HMGN1 as a biomarker for pan- - cancer analysis.

Identification of clinical prognostic factors and analysis of ferroptosis-related gene signatures in the bladder cancer immune microenvironment

BackgroundBladder cancer (BLCA) is a prevalent malignancy affecting the urinary system and poses a significant burden in terms of both incidence and mortality rates on a global scale. Among all BLCA cases, non-muscle invasive bladder cancer constitutes approximately 75% of the total. In recent years, the concept of ferroptosis, an iron-dependent form of regulated cell death marked by the accumulation of lipid peroxides, has captured the attention of researchers worldwide. Nevertheless, the precise involvement of ferroptosis-related genes (FRGs) in the anti-BLCA response remains inadequately elucidated.MethodsThe integration of BLCA samples from the TCGA and GEO datasets facilitated the quantitative evaluation of FRGs, offering potential insights into their predictive capabilities. Leveraging the wealth of information encompassing mRNAsi, gene mutations, CNV, TMB, and clinical features within these datasets further enriched the analysis, augmenting its robustness and reliability. Through the utilization of Lasso regression, a prediction model was developed, enabling accurate prognostic assessments within the context of BLCA. Additionally, co-expression analysis shed light on the complex relationship between gene expression patterns and FRGs, unraveling their functional relevance and potential implications in BLCA.ResultsFRGs exhibited increased expression levels in the high-risk cohort of BLCA patients, even in the absence of other clinical indicators, suggesting their potential as prognostic markers. GSEA revealed enrichment of immunological and tumor-related pathways specifically in the high-risk group. Furthermore, notable differences were observed in immune function and m6a gene expression between the low- and high-risk groups. Several genes, including MYBPH, SOST, SPRR2A, and CRNN, were found to potentially participate in the oncogenic processes underlying BLCA. Additionally, CYP4F8, PDZD3, CRTAC1, and LRTM1 were identified as potential tumor suppressor genes. Significant discrepancies in immunological function and m6a gene expression were observed between the two risk groups, further highlighting the distinct molecular characteristics associated with different prognostic outcomes. Notably, strong correlations were observed among the prognostic model, CNVs, SNPs, and drug sensitivity profiles.ConclusionsFRGs are associated with the onset and progression of BLCA. A FRGs signature offers a viable alternative to predict BLCA, and these FRGs show a prospective research area for BLCA targeted treatment in the future.

Comparative structural studies on Bovine papillomavirus E6 oncoproteins: Novel insights into viral infection and cell transformation from homology modeling and molecular dynamics simulations.

Bovine papillomavirus (BPV) infects cattle cells worldwide, leading to hyperproliferative lesions and the potential development of cancer, driven by E5, E6, and E7 oncoproteins along with other cofactors. E6 oncoprotein binds experimentally to various proteins, primarily paxillin and MAML1, as well as hMCM7 and CBP/p300. However, the molecular and structural mechanisms underlying BPV-induced malignant transformation remain unclear. Therefore, we have modeled the E6 oncoprotein structure from non-oncogenic BPV-5 and compared them with oncogenic BPV-1 to assess the relationship between structural features and oncogenic potential. Our analysis elucidated crucial structural aspects of E6, highlighting both conserved elements across genotypes and genotype-specific variations potentially implicated in the oncogenic process, particularly concerning primary target interactions. Additionally, we predicted the location of the hMCM7 binding site on the N-terminal of BPV-5 E6. This study enhances our understanding of the structural characteristics of BPV E6 oncoproteins and their interactions with host proteins, clarifying structural differences and similarities between high and low-risk BPVs. This is important to understand better the mechanisms involved in cell transformation in BPV infection, which could be used as a possible target for therapy.

TARDBP is a candidate diagnostic biomarker promoting tumor progression via impacting tumor immunity and tumor microenvironment.

In the realm of cancer research, particularly hepatocellular carcinoma (HCC), TAR DNA-binding protein (TARDBP) has transitioned from being associated with neurodegenerative diseases to emerging as a significant molecule in oncology due to its aberrant expression in HCC and other malignancies. This shift underlines the versatility of TARDBP and its critical role in tumorigenesis. Our study illuminates TARDBP's universal upregulation across various cancers, indicating its involvement in fundamental oncogenic processes and potential impact on genomic instability. The relationship between TARDBP expression and tumor mutational burden (TMB) across several cancers highlights its influence on a key hallmark of cancer progression. Additionally, TARDBP's interaction with immune and inflammatory factors within the tumor microenvironment, including its association with immune-stimulatory factors and inverse relationship with immune inhibitors, suggests its role in modulating immune evasion. Clinically, TARDBP's aberrant expression correlates with adverse patient outcomes in HCC, making it a promising candidate for therapeutic targeting. The study concludes that TARDBP holds significant potential as a novel therapeutic target in HCC and possibly other malignancies, meriting further exploration to integrate TARDBP-targeted therapies into cancer treatment protocols, thereby advancing the field of precision medicine.

Targeting CD38 with monoclonal antibodies disrupts key survival pathways in paediatric Burkitt's lymphoma malignant B cells.

Paediatric Burkitt's lymphoma (pBL) is the most common childhood non-Hodgkin B-cell lymphoma. Despite the encouraging survival rates for most children, treating cases with relapse/resistance to current therapies remains challenging. CD38 is a transmembrane protein highly expressed in pBL. This study investigates the effectiveness of CD38-targeting monoclonal antibodies (mAbs), daratumumab and isatuximab, in impairing crucial cellular processes and survival pathways in pBL malignant cells. In silico analyses of patient samples, combined with in vitro experiments using the Ramos cell line, were conducted to assess the impact of daratumumab and isatuximab on cellular proliferation, apoptosis and the phosphoinositide 3-kinase (PI3K) pathway. Isatuximab was found to be more effective than daratumumab in disrupting B-cell receptor signalling, reducing cellular proliferation and inducing apoptosis. Additionally, isatuximab caused a significant impairment of the PI3K pathway and induced metabolic reprogramming in pBL cells. The study also revealed a correlation between CD38 and MYC expression levels in pBL patient samples, suggesting CD38 involvement in key oncogenic processes. The study emphasises the therapeutic potential of CD38-targeting mAbs, particularly isatuximab, in pBL.