Dataset Information

Exosomes from EGFR-Mutated Adenocarcinoma Induce a Hybrid EMT and MMP9-Dependant Tumor Invasion.

ABSTRACT: Exosomes, a class of extra cellular nano-sized vesicles (EVs), and their contents have gained attention as potential sources of information on tumor detection and regulatory drivers of tumor progression and metastasis. The effect of exosomes isolated from patients with an Epidermal Growth Factor Receptor (EGFR)-mutated adenocarcinoma on the promotion of epithelial-mesenchymal transition (EMT) and invasion were examined. Exosomes derived from serum of patients with EGFR-mutated non-small cell lung cancer (NSCLC) mediate the activation of the Phosphoinositide 3-kinase (PI3K)/AKT/ mammalian target of rapamycin (mTOR) pathway and induce an invasion through the up-regulation of matrix metalloproteinase-9 (MMP-9) in A549 cells. We observed a significant increase in the expression of vimentin, a mesenchymal marker, while retaining the epithelial characteristics, as evidenced by the unaltered levels of E-cadherin and Epithelial cell adhesion molecule (EPCAM). We also observed an increase of nuclear factor erythroid 2-related factor 2 (NFR2) and P-cadherin expression, markers of hybrid EMT. Exosomes derived from EGFR-mutated adenocarcinoma serum could be a potential mediator of hybrid EMT and tumor invasion. Understanding how cancerous cells communicate and interact with their environment via exosomes will improve our understanding of lung cancer progression and metastasis formation.

SUBMITTER: Jouida A

PROVIDER: S-EPMC9367273 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Exosomes from EGFR-Mutated Adenocarcinoma Induce a Hybrid EMT and MMP9-Dependant Tumor Invasion.

Jouida Amina A O'Callaghan Marissa M Mc Carthy Cormac C Fabre Aurelie A Nadarajan Parthiban P Keane Michael P MP

Cancers 20220803 15

Exosomes, a class of extra cellular nano-sized vesicles (EVs), and their contents have gained attention as potential sources of information on tumor detection and regulatory drivers of tumor progression and metastasis. The effect of exosomes isolated from patients with an Epidermal Growth Factor Receptor (EGFR)-mutated adenocarcinoma on the promotion of epithelial-mesenchymal transition (EMT) and invasion were examined. Exosomes derived from serum of patients with EGFR-mutated non- ...[more]

PMID: 35954442

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Project description:BackgroundTargeted therapies have improved survival and quality of life for patients with non-small-cell lung cancer with actionable driver mutations. However, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 gene (HER2, also known as ERBB2) exon 20 insertions (Ex20mut) are characterized by a poor response to currently approved tyrosine kinase inhibitors and immunotherapies. The underlying immune biology is not well understood.Materials and methodsWe carried out messenger RNA expression profiling of lung adenocarcinomas (ADCs) with ERBB2 (n = 19) and EGFR exon 20-insertion mutations (n = 13) and compared these to tumors with classical EGFR mutations (n = 40, affecting EGFR exons 18, 19 or 21) and EGFR/ERBB2 mutation-negative lung ADC (EGFR/ERBB2wt, n = 26) focusing on immunologically relevant transcripts. Tumor-infiltrating immune cells were estimated from gene expression profiles.ResultsCytotoxic cells were significantly lower in EGFR-mutated tumors regardless of the affected exon, while Th1 cells were significantly lower in EGFR-Ex20mut compared to EGFR/ERBB2wt tumors. We assessed the differentially expressed genes of ERBB2-Ex20mut and EGFR-Ex20mut tumors compared to EGFR-Ex18/19/21mut and EGFR/ERBB2wt tumors. Of these, the genes GUSB, HDAC11, IFNGR2, PUM1, RASGRF1 and RBL2 were up-regulated, while a lower expression of CBLC, GBP1, GBP2, GBP4 and MYC was observed in all three comparison groups. The omnibus test revealed 185 significantly (FDR = 5%) differentially expressed genes and we found these four most significant gene expression changes in the study cohort: VHL and JAK1 were overexpressed in ERBB2-Ex20mut and EGFR-Ex20mut tumors compared to both EGFR-Ex18/19/21mut and EGFR/ERBB2wt tumors. RIPK1 and STK11IP showed the highest expression in ERBB2-Ex20mut tumors.ConclusionsTargeted gene expression profiling is a promising tool to read out the characteristics of the tumor microenvironment from routine diagnostic lung cancer biopsies. Significant immune reactivity and specific immunosuppressive characteristics in ERBB2-Ex20mut and EGFR-Ex20mut lung ADC with at least some degree of immune infiltration support further clinical evaluation of immune-modulators as partners of immune checkpoint inhibitors in such tumors.

Project description:BackgroundStudying the mechanism of action of LncRNAs in lung adenocarcinoma (LUAD) is of great importance for an in-depth understanding of the molecular mechanism of lung adeno carcinogenesis and development.ObjectiveThe aim is to identify a long non-coding RNA LINC01117 that is specifically and highly expressed in LUAD cells and to investigate its biological functions and molecular mechanisms in LUAD cells, providing a new potential target for targeting LUAD therapy.MethodsThis study used publicly available data downloaded from The Cancer Genome Atlas (TCGA) database. Construction of siRNA and overexpression plasmid-packed lentiviral constructs were used to knock down and increase the expression of LINC01117 in LUAD cells. The effect of LINC01117 on LUAD cell migration and invasion was verified by scratch assays and Transwell assays. Western blot assays were performed to verify the effect of knocking down LINC01117 expression on key proteins of the EMT process. The effect of overexpression and knockdown LINC01117 expression on key proteins of the EMT process and the nuclear and cytoplasmic distribution of YAP1, a key effector molecule of the Hippo pathway, was verified by Western blot assays.ResultsLINC01117 expression was upregulated in LUAD tissues and cell lines. Clinical correlation and prognostic analyses showed that LINC01117 was associated with poorer clinical features (staging and N classification) and poorer prognosis and could be analyzed as an independent prognostic factor. Cell migration and invasion were significantly inhibited in the knockdown group compared to the control group; in contrast, cell migration and invasion were promoted in the overexpression group. Overexpression of LINC01117 resulted in down-regulation of E-cadherin expression and increased expression levels of N-cadherin, vimentin, ZEB1, snail and slug; in contrast, knockdown of LINC01117 appeared to have the opposite effect. Furthermore, knockdown of LINC01117 increased the enrichment of YAP1 protein in the cytoplasm and reduced its level in the nucleus; overexpression of LINC01117 produced the opposite intracellular distribution results.ConclusionsLINC01117 was highly expressed in LUAD, and knockdown of LINC01117 significantly inhibited the migration and invasion of LUAD cells, while overexpression of LINC01117 significantly promoted the migration and invasion of LUAD cells, and affected the EMT process, and was able to alter the distribution of YAP1 in the nucleus and cytoplasm. This suggests that LINC01117 may regulate the activity of the Hippo pathway by altering the nuclear and cytoplasmic distribution of YAP1, which in turn induces the EMT process in lung adenocarcinoma cells and thus exerts a pro-cancer effect. It suggests that LINC01117 may play a key role in the occurrence and development of LUAD.

Dataset Information

Exosomes from EGFR-Mutated Adenocarcinoma Induce a Hybrid EMT and MMP9-Dependant Tumor Invasion.

Publications

Exosomes from <i>EGFR</i>-Mutated Adenocarcinoma Induce a Hybrid EMT and MMP9-Dependant Tumor Invasion.

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