Pathogenesis Of Tumors Research Articles

CCL5 might be a prognostic biomarker and associated with immuno-therapeutic efficacy in cancers: A pan-cancer analysis

PurposeChemokine ligand 5 (CCL5), a vital member of the CC chemokine family, plays diverse roles in tumorigenesis, metastasis, and prognosis in various human tumors. However, no pan-cancer analysis has been conducted to illustrate its distinctive effects on clinical prognosis via underlying mechanisms and biological characteristics. MethodsHerein, we exploited the existed public bioinformatics database, primarily TCGA database and GTEx data, to comprehensively analyze the value of CCL5 involved in patient prognosis. ResultsThis study found that CCL5 was excessively expressed in most tumors and significantly associated with clinical prognosis in 10 out of 33 types of tumors. Notably, CCL5 might be an independent predictive biomarker of clinical outcome in SKCM patients, confirmed by univariate and multivariate Cox regression analysis. Furthermore, we acquired the genetic alteration status of CCL5 in multiple types of tumor tissues from TCGA cohorts. We revealed a potential correlation between the expression level of CCL5 and tumor mutational burden in 33 types of tumors. In addition, data showed that DNA methylation was associated with CCL5 gene expression in THCA, PRAD, LUSC, and BRCA cancers. Immune infiltration and immune checkpoints are fine indexes for evaluating immunotherapy. We uncovered that CCL5 was negatively correlated with the immune infiltration of CD8+ T cell, CD4+ T cell, macrophages, and gamma delta T cells in BRCA-basal and CESC tumors, while a significant positive correlation was observed in BLCA, COAD and other 7 types of tumors. Besides, CCL5 was closely associated with the immune checkpoint molecules in 8 types of tumors. The TIDE score was less in the CCL5 high-expressed group than in the CCL5 low-expressed group in SKCM patients, which indicated that CCL5 might be a fine monitor of immune response for immunotherapy. GO enrichment analysis data uncovered that cytokine-cytokine receptor interaction and chemokine signaling might be involved in the role of CCL5 in regulating tumor pathogenesis and prognosis. ConclusionIn conclusion, CCL5 was preliminarly identified as a biomarker of immune response and prognosis for tumors patients via our first comprehensive pan-cancer analysis.

ADSVAE: An Adaptive Density-aware Spectral Clustering Method for Multi-omics Data Based on Variational Autoencoder

Introduction: The discovery of tumor subtypes helps to explore tumor pathogenesis, determine the operability of clinical treatment, and improve patient survival. Clustering analysis is increasingly applied to multi-genomic data. However, due to the diversity and complexity of multi-omics data, developing a complete clustering algorithm for tumor molecular typing is still challenging. Methods: In this study, we present an adaptive density-aware spectral clustering method based on a variational autoencoder (ADSVAE). ADSVAE first learns the underlying spatial information of each omics data using a variational autoencoder (VAE) based on the Wasserstein distance metric. Secondly, a similarity matrix is built for each gene set using an adaptive density-aware kernel. Thirdly, tensor product graphs (TPGs) are used to merge different data sources and reduce noise. Finally, ADSVAE employs a spectral clustering algorithm and utilizes the Gaussian mixture model (GMM) to cluster the final eigenvector matrix to identify cancer subtypes. Results: We tested ADSVAE on 5 TCGA datasets, all with good performance in comparison with several advanced multi-omics clustering algorithms. Compared with the existing multi-group clustering algorithms, the variational autoencoder based on the Wasserstein distance measure in the ADSVAE algorithm can learn the underlying spatial information on each omics data, which has a better effect on learning complex data distribution. The self-tuning density-aware kernel used by the ADSVAE algorithm enhances the similarity between shared near neighbor points, and the process of tensor product plot data integration and diffusion can better reduce the noise and reveal the underlying structure, improving the performance. Conclusion: Due to the inherent pitfalls of computational biology in the study of cancer subtype identification, although some research conclusions have been made in this paper on the related issues, as the research in related fields continues to deepen, the clustering study of cancer subtype identification based on genomic data needs further improvement and refinement.

PANORAMA OF GASTRIC AND INTESTINAL CARCINOGENESIS: LITERATURE REVIEW

Purpose. The aim of the review is to analyze the modern data on the molecular mechanisms of stomach and intestinal carcinogenesis, which can be the basis for managing of malignant stomach and intestine neoplasms mortality risks’ reduction.
 Materials and methods. The review includes data from foreign and domestic studies published in the electronic bibliographic databases PubMed, Cyberleninka, Elibrary over the past 10 years.
 Results. It is given the analysis of Wnt and β-catenin gene family role in the pathogenesis of stomach and colon malignant tumors and the carcinogenic potential of Helicobacter pylori in gastric cancer, as well as the driver bacteria contributing to the development of colon cancer.
 Conclusion. Stomach cancer and colon cancer are heterogeneous diseases with diverse molecular and histological subtypes, having both similarities and differences in the patterns of cancer promotion. Progress in transparency genesis of these diseases is associated with an understanding of cytotoxic and genotoxic effects, oxidative stress and chronic inflammation mechanisms.

Pathogenesis of salivary gland neoplasms: The concepts of histogenesis and morphogenesis

Many features overlap between different salivary gland neoplasms (SGNs) and as a result, classifying them distinctly has always been challenging. The differences in pathogenesis give rise to variations in the histopathological morphology of the SGNs. More accurate classification of SGNs can be made if the underlying pathogenesis is adequately understood in these terms. The present review aims to elaborate on the classification of SGNs based on the concepts of histogenesis and morphogenesis. In tumor pathology, histogenesis corresponds to the origin of the neoplastic cells; whereas morphogenesis refers to the development of the shape of an organ. The type of cell in which neoplastic transformation has occurred governs the events that follow the initiation of the multistage process which results in neoplasia. Our review elucidates the pathogenesis of the salivary gland tumor to understand the resulting histopathology, tumor morphology, and cellular differentiation of the tumor which reflects the parent cell. It comprehensively covers histogenesis, morphogenesis, and their relevance to the common salivary gland tumors, along with a brief account of the immunohistochemical markers.

Doublecortin-likekinase3(DCLK3)isassociatedwithbadclinicaloutcomeofpatientswithgastriccancerandregulatestheferroptosisandmitochondriafunctioninvitroandinvivo.

Doublecortin-like kinase 3 (DCLK3), a member of tubulin superfamily, has been proved to be closely associated with the pathogenesis of numerous human tumors. However, the expression pattern and regulatory mechanisms of DCLK3 in gastric cancer (GC) remain unknown. DCLK3 expression in GC cells was assessed by RT-qPCR and western blotting. The correlation between DCLK3 levels and the overall survival of GC patients was assessed via TCGA, ACLBI, and Kaplan-Meier plotter databases. Additionally, key proteins (TCF4) involved in the regulation of DCLK3 on GC progression were screened by ACLBI database. Cell proliferation, ferroptotic cell death, and oxidative stress markers were measured by EdU staining, immunofluorescence, ELISA, and western blotting assays. DCLK3 was upregulated in GC, and high DCLK3 expression was significantly associated with poor survival of GC patients. Here, DCLK3 knockdown reduced GC cell proliferation, induced ferroptotic cell death, and exacerbated oxidative stress level. Logistic regression analysis showed that TCF4 was an independent prognostic indicator of GC. Mechanistically, DCLK3 promoted TCF4 expression and subsequently upregulated the expression of TCF4 downstream target genes (c-Myc and Cyclin D1). Furthermore, DCLK3 overexpression enhanced GC cell proliferation, but mitigating ferroptotic cell death and oxidative stress. The regulatory mechanism may involve the upregulation of TCF4, c-Myc, and cyclin D1. Our research suggests that DCLK3 modulates the levels of iron and reactive oxygen and may involve regulation of TCF4 pathway, thereby promoting the GC cell growth, indicating that DCLK3 may use as a prognostic marker and therapeutic target for GC patients.

Amounts of tissue magnesium and some trace elements in cats with mammary tumors related to various clinicopathological parameters

BackgroundMammary tumors are one of the major malignancies seen in cats. Researchers have indicated the similarity between the epidemiological and clinicopathological patterns of feline mammary tumors and human breast cancer (HBC). In recent years, the investigation of trace elements in cancer tissues becomes prevalent in HBC due to the role of these elements in biochemical and physiological processes. This study, it is aimed to evaluate some trace elements in feline mammary tumors according to clinical and pathological findings. MethodsA total of 60 tumoral masses from 16 female cats with mammary tumors were included in the study. The study groups were formed according to histopathology as malignant epithelial tumor (MET; n = 39) and hyperplasia and dysplasia (H&D; n = 21). Copper (Cu), Iron (Fe), Magnesium (Mg), Manganese (Mn), Selenium (Se) and Zinc (Zn) trace elements in mammary tissues were analyzed by using an inductively coupled plasma-optical emission spectrophotometer. ResultsThe mean age and weight of the cats were 11.75 ± 0.75 years and 3.35 ± 0.21 kg; respectively. Eleven of 16 cats were intact whereas the rest of them had been spayed. Metastases were observed in 10 cats. Tissue Mg level in group MET was significantly higher than in group H&D (P < 0.01) while the other elements had not significant differences between the groups. In group MET, analyzed elements were not statistically significant related to the inflammation, ulceration and invasion to the peripheral muscle (P > 0.05). However, tissue Fe level was significantly higher in T2 than in T3 (P < 0.05). The mean levels of tissue Fe, Mg and Mn had significant differences related to histological grading as P < 0.01, P < 0.05 and P < 0.001; respectively. A mild to severe correlation was found between tissue Zn and Se, Cu, Fe, Mg, and Mn levels. ConclusionTissue Mg and some trace elements were evaluated in feline mammary tumours in regard to various clinicopathological parameters. Tissue Mg level was sufficient to differentiate the malignant epithelial tumors from hyperplasia and dysplasia. However, Mn and Se tended to distinguish different tumor types. Tissue Fe, Mg and Mn had significant differences related to histological grading. Also, the Fe level was significantly higher in T2 than in T3 and Zn level tended to be higher in T3 than in T1. It was concluded that Mg, Se, Mn, Fe, Cu and Zn provided useful information on the pathogenesis of feline mammary tumors. Further research is needed on the tissue and serum concentrations of trace elements which may provide valuable information for the disease prognosis.

A Call for Discovery and Therapeutic Development for Cutaneous Neurofibromas

A Call for Discovery and Therapeutic Development for Cutaneous Neurofibromas

Serum Metabolite Biomarkers for Pancreatic Tumors: Neuroendocrine and Pancreatic Ductal Adenocarcinomas-A Preliminary Study.

Pancreatic cancer is the most common pancreatic solid malignancy with an aggressive clinical course and low survival rate. There are a limited number of reliable prognostic biomarkers and a need to understand the pathogenesis of pancreatic tumors; neuroendocrine (PNET) and pancreatic ductal adenocarcinomas (PDAC) encouraged us to analyze the serum metabolome of pancreatic tumors and disturbances in the metabolism of PDAC and PNET. Using the AbsoluteIDQ® p180 kit (Biocrates Life Sciences AG, Innsbruck, Austria) with liquid chromatography-mass spectrometry (LC-MS), we identified changes in metabolite profiles and disrupted metabolic pathways serum of NET and PDAC patients. The concentration of six metabolites showed statistically significant differences between the control group and PDAC patients (p.adj < 0.05). Glutamine (Gln), acetylcarnitine (C2), and citrulline (Cit) presented a lower concentration in the serum of PDAC patients, while phosphatidylcholine aa C32:0 (PC aa C32:0), sphingomyelin C26:1 (SM C26:1), and glutamic acid (Glu) achieved higher concentrations compared to serum samples from healthy individuals. Five of the tested metabolites: C2 (FC = 8.67), and serotonin (FC = 2.68) reached higher concentration values in the PNET serum samples compared to PDAC, while phosphatidylcholine aa C34:1 (PC aa C34:1) (FC = -1.46 (0.68)) had a higher concentration in the PDAC samples. The area under the curves (AUC) of the receiver operating characteristic (ROC) curves presented diagnostic power to discriminate pancreatic tumor patients, which were highest for acylcarnitines: C2 with AUC = 0.93, serotonin with AUC = 0.85, and PC aa C34:1 with AUC = 0.86. The observations presented provide better insight into the metabolism of pancreatic tumors, and improve the diagnosis and classification of tumors. Serum-circulating metabolites can be easily monitored without invasive procedures and show the present clinical patients' condition, helping with pharmacological treatment or dietary strategies.

Differential expression levels of β-catenin are associated with invasive behavior of both functional and non-functional pituitary neuroendocrine tumor (PitNET).

Although research continues to elucidate the molecular mechanism underlying pituitary tumor pathogenesis, limited information is available on the potential role and expression profile of β-catenin in functional and non-functional pituitary neuroendocrine tumors (PitNETs). In the current study, 104 pituitary samples (tumors and cadaveric healthy pituitary tissues) were included and the gene and protein expression levels of β-catenin were assessed by Real-Time PCR and immunohistochemistry, respectively. The correlation between expression level of β-catenin and tumor invasive feature and size as well as patient age, gender, and hormonal level was measured. The data showed that PitNET samples expressed higher levels of the β-catenin gene and protein compared to healthy pituitary tissues. Although there was no difference in β-catenin expression level between non-functioning (NF-PitNETs) and growth hormone-producing tumors (GH-PitNETs), both tumor types showed significantly elevated β-catenin levels compared to healthy pituitary tissues. The high level of β-catenin in the invasive functional and non-functional tumors is indicative of the association of β-catenin with PitNETs invasion. The expression pattern of the β-catenin gene and protein was consistently and significantly associated with these tumor types. The correlation between β-catenin and insulin-like growth factor 1 (IGF-1) in GH-PitNETs indicates the potential relevance of β-catenin and IGF-1 for GH-PitNETs. The simultaneous increase in the expression of β-catenin gene and protein level in PitNET tissues and their relationship to the tumor severity indicates the possible contributing role of β-catenin and its underlying signaling mediators in PitNET pathogenesis.

MBD3 as a Potential Biomarker for Colon Cancer: Implications for Epithelial-Mesenchymal Transition (EMT) Pathways.

The tumor EMT is a crucial event in tumor pathogenesis and progression. Previous research has established MBD3's significant role in pancreatic cancer EMT. However, MBD3's precise role in colon cancer remains unclear and warrants further investigation. Pan-cancer analysis revealed MBD3's differential expression in various tumors and its significant association with tumor occurrence, growth, and progression. Moreover, analysis of single-cell sequencing and clinical data for colon cancer revealed MBD3 expression's negative correlation with clinical indicators such as survival prognosis. Functional enrichment analysis confirmed the association between MBD3 and EMT in colon cancer. Pathological examinations, western blotting, and qRT-PCR in vitro and in vivo validated MBD3's differential expression in colon cancer. Transwell, CCK-8, clone formation, and in vivo tumorigenesis experiments confirmed MBD3's impact on migration, invasion, and proliferation. Our findings demonstrate MBD3 as a potential prognostic marker and therapeutic target for colon cancer.

BIOL-17. DISSECTING THE EXPRESSION AND FUNCTION OF ANGIOPOIETIN-1 IN PEDIATRIC BRAIN TUMORS

Abstract BACKGROUND Angiopoietin-1 (Angpt1) is a secreted protein that promotes angiogenesis and vascular stability in development and certain disease states through activation of the Tie2 receptor. However, little is known about its expression or function within pediatric brain tumors. METHODS We utilized available datasets from patient samples and created murine models of pediatric high-grade glioma and ependymoma by in utero electroporation. Using a combination of transcriptomics and Angpt1-GFP reporter tumor models we evaluated Angpt1 expression across different types of pediatric brain tumors. We also applied inducible Angpt1 floxed mice to generate tumor-specific knock-out models. RESULTS Angpt1 is upregulated in glial brain tumors, including high-grade gliomas and ependymomas. We find Angpt1 is expressed by specific cell populations within gliomas and ependymomas, along with non-tumor reactive astrocytes and perivascular mural cells. Leveraging our in vivo brain tumor platform we have created tumor specific Angpt1 knock-out models by including a plasmid expressing Cre-recombinase. Ongoing studies aim to delineate the function of Angpt1 in tumor pathogenesis, including tumor angiogenesis and blood-brain barrier function. CONCLUSION Current work finds that Angpt1 is upregulated in glial brain tumors and nominates it as a potential modulator of brain tumor vascular biology, including tumor angiogenesis and permeability.

Role of Histone Deacetylases in the Pathogenesis of Salivary Gland Tumors and Therapeutic Targeting Options.

Salivary gland tumors (SGTs) comprise a rare and heterogenous category of benign/malignant neoplasms with progressively increasing knowledge of the molecular mechanisms underpinning their pathogenesis, poor prognosis, and therapeutic treatment efficacy. Emerging data are pointing toward an interplay of genetic and epigenetic factors contributing to their heterogeneity and diverse clinical phenotypes. Post-translational histone modifications such as histone acetylation/deacetylation have been shown to actively participate in the pathobiology of SGTs, further suggesting that histone deacetylating factors (HDACs), selective or pan-HDAC inhibitors (HDACis), might present effective treatment options for these neoplasms. Herein, we describe the molecular and epigenetic mechanisms underlying the pathology of the different types of SGTs, focusing on histone acetylation/deacetylation effects on gene expression as well as the progress of HDACis in SGT therapy and the current status of relevant clinical trials.

Involvement of NY-ESO-1 and MAGE-A4 in the pathogenesis of desmoid tumors.

The involvement of New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and melanoma-associated antigen A4 (MAGE-A4) in soft-tissue sarcoma pathogenesis has recently been reported; however, their involvement in desmoid tumors (DTs) remains unknown. This study aimed to determine the involvement of NY-ESO-1 and MAGE-A4 in DTs. Immunostaining for β-catenin, NY-ESO-1, and MAGE-A4 was performed on DT biopsy specimens harvested at our institution. The positivity rate for each immune component was calculated. In addition, the correlations between the positivity rates for the immune molecules were investigated. The correlation between the positivity rate and age or longest diameter of each immune molecule was also investigated. β-catenin showed staining mainly in the tumor cell nuclei of DTs. Both NY-ESO-1 and MAGE-A4 showed staining in the nucleus, cytoplasm, and infiltrating lymphocytes of DT cells. The mean positive cell rates for β-catenin, NY-ESO-1, and MAGE-A4 were 43.9 ± 21.7, 30 ± 21.6, and 68.9 ± 20.8, respectively. A strong negative correlation was observed between β-catenin and MAGE-A4 positivity rates (r = -0.64). The positivity rates for NY-ESO-1 and MAGE-A4 showed a moderate positive correlation (r = -0.42). A very strong negative correlation was observed between age and the NY-ESO-1 positivity rate (r = -0.72). A weak negative correlation was observed between age and the MAGE-A4 positivity rate (r = -0.28). A medium negative correlation was observed between the longest tumor diameter and NY-ESO-1 positivity (r = -0.37). NY-ESO-1 and MAGE-A4 may be involved in the DT microenvironment. Thus, NY-ESO-1 and MAGE-A4 may be useful in the diagnosis of DT.

Updating germ cell tumour pathogenesis - the ability of seminomas for FOXA2-driven extra-embryonic differentiation.

Testicular germ cell tumours are the most common solid malignancies in young men of age 14-44 years. It is generally accepted that both seminomas and non-seminomas arise from a common precursor, the germ cell neoplasia in-situ, which itself is the result of a defective (primordial) germ cell development. The stem cell-like population of the non-seminomas, the embryonal carcinoma, is capable of the differentiation of all three germ layers (teratomas) and extra-embryonic tissues (yolk-sac tumours, choriocarcioma) into cells. In contrast, seminomas are thought to have a limited differentiation potential. Nevertheless, several studies have highlighted their ability to undergo reprogramming to an embryonal carcinoma or differentiation into other non-seminomatous entities. Here, we demonstrate that in approximately 5% of seminomas, the yolk-sac tumour driver gene FOXA2 is detectable at the protein level, indicative of an occult yolk-sac tumour subpopulation that putatively arose from seminoma cells, as the presence of other GCT entities could be excluded. The presence of these subpopulations might render the tumour more aggressive and argue for an adjustment of the therapeutic concept. We used our data to update the model of germ cell tumour pathogenesis, especially regarding the developmental potential of seminomas. Additionally, we suggest to include detection of FOXA2 into standard routine diagnosis of seminomas.

SGN-B6A, an integrin beta-6 (ITGB6)-targeted antibody-drug conjugate (ADC), in patients with advanced solid tumors: Updated results from a phase 1 study (SGNB6A-001).

3024 Background: The receptor ITGB6 plays a role in tumor pathogenesis and invasiveness, and its overexpression is correlated with poor outcomes. Non-small cell lung cancer (NSCLC), head and neck (HNSCC), and esophageal cancer (EC) are among tumors with high ITGB6 expression (Lyon 2021). SGN-B6A is an ITGB6-directed vedotin ADC with a monomethyl auristatin E (MMAE) payload. SGN-B6A elicits antitumor activity via MMAE-mediated cytotoxicity, bystander effect, and immunogenic cell death. Here, we present updated results of an ongoing phase 1 study with a focus on NSCLC, HNSCC, and EC (Hollebecque SITC 2022). Methods: SGNB6A-001 (NCT04389632) is an open-label, multicenter, dose-escalation/expansion study evaluating the safety, pharmacokinetics, and antitumor activity of SGN-B6A (per RECIST v1.1) in patients (pts) with advanced solid tumors. Dose escalation (Part A) explored continuous weekly and intermittent dosing regimens. Dose was calculated using total body weight (TBW) or adjusted ideal body weight. Dose expansion (Part B) is enrolling pts with NSCLC, HNSCC, and EC. Results: As of 14 December 2022, 148 pts received SGN-B6A, 88 pts in Part A and 60 pts in Part B; enrollment for Part A is complete. In all cohorts (N=148), treatment-emergent adverse events (TEAEs) were observed in 88.5% of pts: 50.7% were Grade ≥ 3 (21.6% related), and 37.2% were serious (8.1% related); 6.1% of pts discontinued treatment due to TEAEs. 3 pts (2.0%) died due to TEAEs; none of the deaths were considered treatment-related. The most common TEAE was fatigue (35.1%); the most common Grade ≥ 3 TEAE was neutropenia (8.1%); the most common TEAEs leading to treatment discontinuation were peripheral sensory neuropathy and pneumonia (1.4% each). Prior lines of therapy and efficacy data for Part A (NSCLC, EC, and HNSCC) and Part B (HNSCC) subsets are summarized. Conclusions: SGN-B6A demonstrated a manageable safety profile, and showed encouraging preliminary antitumor activity and response durability in dose escalation in a heavily pretreated population. Part B dose expansion cohorts in NSCLC, esophageal squamous cell carcinoma (ESCC), and HNSCC are ongoing. Clinical trial information: NCT04389632 . [Table: see text]

Metabolic insights into tumor pathogenesis: Unveiling pan‐cancer metabolism and the potential of untargeted metabolomics

AbstractMetabolic dysregulation is a hallmark of cancer, underpinning diverse aggressive behaviors such as uncontrolled proliferation, immune evasion, and metastasis. Despite the potential of tumor metabolites as biomarkers, their utility has been hampered by metabolic heterogeneity. Exploring cancer metabolism aims to discern shared metabolic pathways and have a better understanding the metabolic heterogeneity of tumors. This approach offers a holistic view of cancer metabolism, facilitating the identification of multicancer‐relevant metabolic targets and the development of more broadly effective therapeutics. In this review, we present a comprehensive overview of the current landscape of cancer metabolism and its prospective applications in cancer diagnosis and prognosis. We delineate common metabolic aberrations observed across a spectrum of cancer types and elucidate the unique metabolic signatures characterizing the six leading causes of cancer‐related mortality. Furthermore, we survey the utilization of untargeted metabolomics and single‐cell technologies in cancer screening, diagnosis, and prognosis, while also spotlighting available data resources for pan‐cancer metabolomics analyses. Throughout this discussion, we tackle prevailing research challenges and propose strategies aimed at enhancing cancer management. Our objective is to furnish valuable insights that can inform and guide future research endeavors in the dynamic realm of cancer metabolism.

Assessment of the differential profile of breast intratumoral bacteria in treatment responders and nonresponders.

580 Background: Despite improvements in breast cancer therapy, many patients do not respond to treatment: the response rate varies between 31 and 80% [Walks et al., 2019]. The tumor microenvironment contains a microbiome which is both cancer type-specific and different to surrounding normal tissue [Nejman et al., 2020]. It plays an important role in tumour microenvironment crosstalk with tumor cells and has been implicated in disease pathogenesis, being recognised in the latest hallmarks of cancer [Hanahan et Weinberg, 2011]. It has also successfully predicted treatment response [Chen et al., 2022; Hermida et al., 2022]. Here, we use conventional microbiome analysis alongside our proprietary mechanistically-powered technology platform to compare the intratumoral bacteria between responders and non-responders. We hypothesise that there are significant differences between those groups regarding composition and mechanistic function of the bacteria. Methods: The tumor microbiome can be deduced from existing sequencing data of tumor biopsy samples. Using 34 tumor DNA samples from 5 breast cancer studies, we compared the intratumoral bacterial profiles of responders to non-responders of various treatments. We performed microbiome analysis in R, including alpha diversity, compositional abundance profiles, and PERMANOVA (permutational analysis of variance). Additionally, BioCorteX CarbonMirror version dated 2023-02-14 was used to infer mechanistic links between bacterial species and the up- and downregulation of genes implicated in the hallmarks of cancer. Results: The results show significant differences in diversity and compositional profile between responders and non-responders: Non-responders have significantly higher alpha diversity ( p&lt;0.05) and a higher proportion of Proteobacteria. PERMANOVA analysis revealed that while responders are more likely to have commensal bacteria, non-responder tumour microbiomes are more likely to harbor pathogenic species such as Mycoplasmopsis fermentans. Mechanistic analysis showed that for all responders the tumor microbiome is consistently promoting tumor suppressor genes and downregulating proto-oncogenes. In non-responders, however, the tumor microbiome is upregulating and downregulating both with unclear consistency. Conclusions: Our results show microbiome differences between responders and non-responders which were mechanistically implicated in tumor pathogenesis. Further analysis divided by the hallmarks of cancer is required to fully understand the non-responder microbiome links. The reported findings could make the tumor microbiome a useful biomarker aiding patient stratification for both prognosis and treatment choice. They also highlight a potentially meaningful mechanistic link between tumour microenvironment and treatment response that could be leveraged as a novel therapeutic avenue.

The YTHDC1/GLUT3/RNF183 axis forms a positive feedback loop that modulates glucose metabolism and bladder cancer progression

Aberrant glucose metabolism is a characteristic of bladder cancer. Hyperglycemia contributes to the development and progression of bladder cancer. However, the underlying mechanism by which hyperglycemia promotes the aggressiveness of cancers, especially bladder cancer, is still incompletely understood. N6-methyladenosine (m6A) modification is a kind of methylation modification occurring at the N6 position of adenosine that is important for the pathogenesis of urological tumors. Recently, it was found that the m6A reader YTHDC1 is regulated by high-glucose conditions. In our study, we revealed that YTHDC1 is not only regulated by high-glucose conditions but is also downregulated in bladder cancer tissue and associated with the prognosis of cancer. We also showed that YTHDC1 suppresses the malignant progression of and the glycolytic process in bladder cancer cells in an m6A-dependent manner and determined that this effect is partially mediated by GLUT3. Moreover, GLUT3 was found to destabilize YTHDC1 by upregulating RNF183 expression. In summary, we identified a novel YTHDC1/GLUT3/RNF183 feedback loop that regulates disease progression and glucose metabolism in bladder cancer. Collectively, this study provides new insight regarding the pathogenesis of bladder cancer under hyperglycemic conditions and might reveal ideal candidates for the development of drugs for bladder cancer.

A novel protein encoded by circUBE4B promotes progression of esophageal squamous cell carcinoma by augmenting MAPK/ERK signaling

Esophageal squamous carcinoma (ESCC) is a common malignant cancer. Although the non-coding roles of circRNAs in the pathogenesis of human tumors have been well studied, whether circRNAs participate in the progression of ESCC by encoding novel proteins remains unclear. In this study, we identified an overexpression circRNA with protein-coding ability in ESCC tissues, called circUBE4B, whose expression level is correlated with tumor size and tumor differentiation level of ESCC patients. Moreover, a higher level of circUBE4B in ESCC patients is correlated with a worse prognosis. Functionally, we found that circUBE4B promoted the proliferation of ESCC cells by encoding a novel cancer-promoting protein, circUBE4B-173aa. Mechanistically, the circUBE4B-173aa protein interacts with MAPK1 and promotes the phosphorylation level of MAPK1 to eventually activate MAPK/ERK signaling pathway. The xenograft model revealed that overexpression of circUBE4B-173aa in ESCC cells significantly promoted the growth of grafts. Our study provides new insights into the mechanism of circRNA in the development of ESCC and circUBE4B-173aa has the potential to serve as a biomarker and a novel therapeutic target for ESCC therapy.

A phase 2 basket trial of ulixertinib (BVD-523) in combination with hydroxychloroquine in patients with advanced gastrointestinal malignancies harboring MAPK pathway mutations (BVD-523-HCQ).

TPS4174 Background: RAS-induced signaling through the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway plays an important role in the pathogenesis of many solid tumors. Ulixertinib (BVD-523) is a first-in-class and best-in-class small molecule inhibitor of ERK 1/2 that is currently being investigated in multiple cancer clinical trials, both as a single agent and as part of combination therapy. Preclinical studies have demonstrated that inhibition of the RAS/MAPK/ERK signaling cascade leads to upregulation of autophagy, a catabolic pathway that includes the lysosomal degradation of proteins to support cellular metabolism during times of cellular stress. Given cancer cells’ increased reliance on autophagy to enhance their survival in this context, this study seeks to evaluate the combination of ulixertinib with hydroxychloroquine, an antimalarial drug known to suppress autophagy, in patients with advanced gastrointestinal malignancies harboring mutations in genes involved in MAPK signaling. Methods: This is an open-label, multicenter, phase II basket study of ulixertinib in combination with hydroxychloroquine in patients with advanced GI malignancies harboring mutations in one of the following MAPK signaling-associated genes: KRAS, NRAS, HRAS, BRAF (non-V600), MEK1/2, or ERK1/2. The completed Phase 1 dose-escalation trial (NCT04145297) established the recommended Phase 2 dose which will be the doses used in this study; ulixertinib 450mg PO BID combined with hydroxychloroquine 600mg PO BID, both drugs administered daily in 28-day cycles, with tumor assessments after every 2 cycles. The trial has five baskets based on primary disease: cholangiocarcinoma, pancreatic adenocarcinoma, colorectal adenocarcinoma, esophageal adenocarcinoma, and gastric adenocarcinoma. A Simon two-stage design will be employed within each of the 5 disease-specific baskets noted above, with the first stage of enrollment consisting of n=13 patients/ basket. To be considered evaluable, a patient must complete at least one cycle of therapy and receive at least 75% of the prescribed dose during that first cycle. If ≥ 4 patients in a specific basket achieve a response (complete or partial), that basket will then open to Stage 2 with enrollment of an additional 30 patients. Primary study endpoints will include safety/toxicity as well as ORR by RECIST 1.1. The secondary endpoint for efficacy is progression-free survival. Exploratory endpoints include pharmacokinetics of both ulixertinib and hydroxychloroquine, as well as predictive biomarkers from blood and tumor tissue-based samples. At the time of abstract submission, 26 of the planned 65 patients in Stage 1 had been enrolled. Clinical trial information: NCT05221320 .