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Tumor microbiome contributes to an aggressive phenotype in the basal-like subtype of pancreatic cancer.

ABSTRACT: Despite the uniform mortality in pancreatic adenocarcinoma (PDAC), clinical disease heterogeneity exists with limited genomic differences. A highly aggressive tumor subtype termed 'basal-like' was identified to show worse outcomes and higher inflammatory responses. Here, we focus on the microbial effect in PDAC progression and present a comprehensive analysis of the tumor microbiome in different PDAC subtypes with resectable tumors using metagenomic sequencing. We found distinctive microbial communities in basal-like tumors and identified an increasing abundance of Acinetobacter, Pseudomonas and Sphingopyxis to be highly associated with carcinogenesis. Functional characterization of microbial genes suggested the potential to induce pathogen-related inflammation. Host-microbiota interplay analysis provided new insights into the tumorigenic role of specific microbiome compositions and demonstrated the influence of host genetics in shaping the tumor microbiome. Taken together, these findings indicated that the tumor microbiome is closely related to PDAC oncogenesis and the induction of inflammation. Additionally, our data revealed the microbial basis of PDAC heterogeneity and proved the predictive value of the microbiome, which will contribute to the intervention and treatment of disease.

SUBMITTER: Guo W

PROVIDER: S-EPMC8408135 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Tumor microbiome contributes to an aggressive phenotype in the basal-like subtype of pancreatic cancer

Project description:Despite the uniform mortality in pancreatic adenocarcinoma (PDAC), clinical disease heterogeneity exists with limited genomic differences. A highly aggressive tumor subtype termed basal-like was identified to show worse outcomes and higher inflammatory responses. Here, we focus on the microbial effect in PDAC progression and present a comprehensive analysis of the tumor microbiome in different PDAC subtypes. Tumors from 62 resectable PDAC patients were subjected to metagenomic sequencing and RNA-seq.

2021-08-30 | GSE172356 | GEO

Tumor microbiome contributes to an aggressive phenotype in the basal-like subtype of pancreatic cancer

Project description:Tumor microbiome contributes to an aggressive phenotype in the basal-like subtype of pancreatic cancer

| PRJNA723013 | ENA

SUMO pathway inhibition targets an aggressive pancreatic cancer subtype.

Project description:OBJECTIVE:Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies. DESIGN:We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC. RESULTS:We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition. CONCLUSION:SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.

| S-EPMC7398468 | biostudies-literature

SERPINB3 induces the aggressive basal-like/squamous subtype and promotes invasion and metastasis in pancreatic cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-10-12 | GSE223909 | GEO

SERPINB3 induces the aggressive basal-like/squamous subtype and promotes invasion and metastasis in pancreatic cancer II

Project description:Pancreatic cancer is a heterogenous disease and consists of distinct subtypes. Here, we searched for candidate driver genes of the basal-like/squamous subtype, a more aggressive molecular subtype of pancreatic ductal adenocarcinoma (PDAC). Through an integrated transcriptome analysis, we identified the serine/cysteine protease inhibitor, SERPINB3 (squamous cell carcinoma antigen 1, SCCA1), as being upregulated in the basal-like/squamous PDAC using a discovery and validation approach. SERPINB3 upregulation associated with decreased patient survival and a transcriptome profile indicative of the basal-like/squamous subtype. The goal of this study was aimed to identify SERPINB3 induced molecular signatures in PDAC.

2023-10-12 | GSE223908 | GEO

SERPINB3 induces the aggressive basal-like/squamous subtype and promotes invasion and metastasis in pancreatic cancer III

2023-10-12 | GSE224564 | GEO

SERPINB3 induces the aggressive basal-like/squamous subtype and promotes invasion and metastasis in pancreatic cancer I

2023-10-12 | GSE223536 | GEO

Expression of Nestin associates with BRCA1 mutations, a basal-like phenotype and aggressive breast cancer.

Project description:We here examined whether Nestin, by protein and mRNA levels, could be a predictor of BRCA1 related breast cancer, a basal-like phenotype, and aggressive tumours. Immunohistochemical staining of Nestin was done in independent breast cancer hospital cohorts (Series I-V, total 1257 cases). Also, TCGA proteomic data (n?=?103), mRNA microarray data from TCGA (n?=?520), METABRIC (n?=?1992), and 6 open access breast cancer datasets (n?=?1908) were analysed. Patients with Nestin protein expression in tumour cells more often had BRCA1 germline mutations (OR 8.7, p?<?0.0005, Series III), especially among younger patients (<40 years at diagnosis) (OR 16.5, p?=?0.003). Nestin protein positivity, observed in 9-28% of our hospital cases (Series I-IV), was independently associated with reduced breast cancer specific survival (HR?=?2.0, p?=?0.035) and was consistently related to basal-like differentiation (by Cytokeratin 5, OR 8.7-13.8, p?<?0.0005; P-cadherin OR 7.0-8.9, p?<?0.0005; EGFR staining, OR 3.7-8.2, p???0.05). Nestin mRNA correlated significantly with Nestin protein expression (??=?0.6, p?<?0.0005), and high levels were seen in the basal-like intrinsic subtype. Gene expression signalling pathways linked to high Nestin were explored, and revealed associations with stem-like tumour features. In summary, Nestin was strongly associated with germline BRCA1 related breast cancer, a basal-like phenotype, reduced survival, and stemness characteristics.

| S-EPMC5430803 | biostudies-literature

INHBA is a mediator of aggressive tumor behavior in HER2+ basal breast cancer.

Project description:BackgroundResistance to HER2-targeted therapeutics remains a significant clinical problem in HER2+ breast cancer patients with advanced disease. This may be particularly true for HER2+ patients with basal subtype disease, as recent evidence suggests they receive limited benefit from standard of care HER2-targeted therapies. Identification of drivers of resistance and aggressive disease that can be targeted clinically has the potential to impact patient outcomes.MethodsWe performed siRNA knockdown screens of genes differentially expressed between lapatinib-responsive and -resistant HER2+ breast cancer cells, which corresponded largely to luminal versus basal subtypes. We then validated hits in 2-d and 3-d cell culture systems.ResultsKnockdown of one of the genes, INHBA, significantly slowed growth and increased sensitivity to lapatinib in multiple basal HER2+ cell lines in both 2-d and 3-d cultures, but had no effect in luminal HER2+ cells. Loss of INHBA altered metabolism, eliciting a shift from glycolytic to oxidative phosphorylative metabolism, which was also associated with a decrease in tumor invasiveness. Analysis of breast cancer datasets showed that patients with HER2+ breast cancer and high levels of INHBA expression had worse outcomes than patients with low levels of INHBA expression.ConclusionsOur data suggest that INHBA is associated with aggressiveness of the basal subtype of HER2+ tumors, resulting in poor response to HER2-targeted therapy and an invasive phenotype. We hypothesize that targeting this pathway could be an effective therapeutic strategy to reduce invasiveness of tumor cells and to improve therapeutic response.

| S-EPMC8898494 | biostudies-literature

Basal microvilli define the metabolic capacity and lethal phenotype of pancreatic cancer.

Project description:Apical microvilli of polarized epithelial cells govern the absorption of metabolites and the transport of fluid in tissues. Previously, we reported that tall and dense basal microvilli present on the endothelial cells of pancreatic cancers, a lethal malignancy with a high metabolism and unusual hypomicrovascularity, contain nutrient trafficking vesicles and glucose; their length and density were related to the glucose uptake of pancreatic cancers in a small-scale analysis. However, the implications of basal microvilli on pancreatic cancers are unknown. Here, we evaluated the clinical implications of basal microvilli in 106 pancreatic cancers. We found that basal microvilli are a dominant change in pancreatic cancers. The presence of longer and denser basal microvilli on the microvessels in pancreatic cancer tissues positively correlated with increased glucose uptake and higher metastatic (or invasive) and proliferative potentials of neoplastic cells and vice versa. Clinically, postoperative patients with longer and denser basal microvilli were more prone to unfavorable pathological characteristics and dismal prognoses. They were even more refractory to adjuvant therapy than those with shorter and thinner basal microvilli were. Our findings show that basal microvilli define the metabolic capacity and lethal phenotype of pancreatic cancers. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

| S-EPMC7898529 | biostudies-literature

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