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Identification of Novel Early Pancreatic Cancer Biomarkers KIF5B and SFRP2 From “First contact” interactions in the Tumor Microenvironment

ABSTRACT: Abstract: Background: Pancreatic cancer is one of the most difficult cancers to detect early and most patients die from complications arising due to distant organ metastases. The lack of bona fide early biomarkers is one of the primary reasons for the late diagnosis of this cancer. It is a multifactorial disease and warrants a novel approach to identify novel early biomarkers. Methods: In order to characterize the proteome, Extracellular vesicles (EVs) isolated from different in vitro conditions mimicking interactions between pancreatic cancer epithelial and stromal cells were analyzed by high throughput mass spectrometry. Biological activity of the secreted EVome was analyzed by investigating changes in distant organ metastases and early changes in the microbiome. Candidate biomarkers (KIF5B, SFRP2, LOXL2, and MMP3) were selected and validated on mouse-human hybrid Tissue Microarray (TMA) that was specifically generated for this study. Additionally, a human TMA was used to analyze the expression of KIF5B and SFRP2 in progressive stages of pancreatic cancer. Results: The EVome of epithelial and stromal cells co-cultured with each other is different from individual cells with distinct protein compositions. EVs secreted from stromal and cancer cells cultures could not induce significant changes in Pre-Metastatic Niche (PMN) modulation assessed by changes in distant organ metastases. However, they did induce significant early changes in the early microbiome, as indicated by changes in α and β-diversities. KIF5B and SFRP2 show promise for early detection and investigation in progressive pancreatic cancer. These markers are expressed in all stages of pancreatic cancer such as low grade PanINs, advanced cancer, and liver and soft tissue metastases. Conclusions: Proteomic characterization of EVs from mimicking conditions of tumor-stromal interactions resulted in the identification of several proteins some for the first time in EVs. These secreted EVs cannot induce changes in distant organ metastases in in vivo models of EV education but modulate early changes in the murine microbiome. Among the proteins that were analyzed (MMP3, KIF5B, SFRP2, and LOXL2) KIF5B and SFRP2 show promise as bona fide early pancreatic cancer biomarkers expressed in progressive stages of pancreatic cancer.

ORGANISM(S): Homo sapiens (human) Mus musculus (mouse)

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PROVIDER: S-BSST794 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Background: The tumor microenvironment (TME) has been reported to have significant value in the diagnosis and prognosis of cancers. This study aimed to identify key biomarkers in the TME of luminal breast cancer (BC). Methods: We obtained immune scores (ISs) and stromal scores (SSs) for The Cancer Genome Atlas (TCGA) luminal BC cohort from the online ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) portal. The relationships between ISs and SSs and the overall survival of luminal BC patients were assessed by the Kaplan-Meier method. The differentially expressed messenger RNAs (DEmRNAs) related to the ISs and SSs were subjected to functional enrichment analysis. Additionally, a competing endogenous RNA (ceRNA) network was constructed with differentially expressed microRNAs (DEmiRNAs) and long noncoding RNAs (DElncRNAs). Furthermore, a protein-protein interaction (PPI) network was established to analyze the DEmRNAs in the ceRNA network. Then, survival analysis of biomarkers involved in the ceRNA network was carried out to explore their prognostic value. Finally, these biomarkers were validated using the luminal BC dataset from the Gene Expression Omnibus (GEO) database. Results: The results showed that ISs were significantly associated with longer survival times of luminal BC patients. Functional enrichment analysis showed that the DEmRNAs were mainly associated with immune response, antigen binding, and the extracellular region. In the PPI network, the top 10 DEmRNAs were identified as hub genes that affected the TME of luminal BC. Finally, two DEmiRNAs, two DElncRNAs, and 17 DEmRNAs of the ceRNA network associated with the TME were shown to have prognostic value. Subsequently, the expression of 15 prognostic biomarkers was validated in one additional dataset (GSE81002). In particular, one lncRNA (GVINP1) and five mRNAs (CCDC69, DOCK2, IKZF1, JCHAIN, and NCKAP1L) were novel biomarkers. Conclusions: Our studies demonstrated that ISs were associated with the survival of luminal BC patients, and a set of novel biomarkers that might play a prognostic role in the TME of luminal BC was identified.

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Identification of Novel Early Pancreatic Cancer Biomarkers KIF5B and SFRP2 From “First contact” interactions in the Tumor Microenvironment

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