Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Integrated mutation, copy number and expression profiling in resectable non-small cell lung cancer

ABSTRACT: Study aims: to identify critical genes involved in non-small cell lung cancer (NSCLC) pathogenesis that may lead to a more complete understanding of this disease and identify novel molecular targets for use in the development of more effective therapies. Methods: Both transcriptional and genomic profiling were performed on 69 resected NSCLC specimens and results correlated with mutational analyses and clinical data to identify genetic alterations associated with groups of interest. Results: Combined analyses identified specific patterns of genetic alteration associated with adenocarcinoma vs. squamous differentiation; KRAS mutation; TP53 mutation, metastatic potential and disease recurrence and survival. Amplification of 3q was associated with mutations in TP53 in adenocarcinoma. A prognostic signature for disease recurrence, reflecting KRAS pathway activation, was validated in an independent test set. Conclusions: These results may provide the first steps in identifying new predictive biomarkers and targets for novel therapies, thus improving outcomes for patients with this deadly disease. Transcriptional profiling of 82 samples of NSCLC using Peter MacCallum in-house 10,500 element cDNA microarray. RNA from 11 pooled cell lines used as reference for each sample. Replicate of 6 samples included.

ORGANISM(S): Homo sapiens

SUBMITTER: Holger Schlueter

PROVIDER: E-GEOD-25326 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Immunogenic cell death (ICD) in cancer represents a functionally unique therapeutic response that can induce tumor-targeting immune responses. ICD is characterized by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which confer adjuvanticity to dying cancer cells. The spatiotemporally defined emission of DAMPs during ICD has been well described; whereas the epigenetic mechanisms that regulate ICD hallmarks have not yet been deeply elucidated. Here, we aimed to examine the involvement of miRNAs and their putative targets taking advantage from well-established in vitro models of ICD. To this end, B cell lymphoma (Mino) and breast cancer (MDA-MB-231) cell lines were exposed to two different ICD inducers: the combination of retinoic acid (RA) and interferon-alpha (IFN-a) and doxorubicin, and to non ICD inducers like gamma irradiation. Then, miRNA and mRNA profiles were studied by next generation sequencing. Co-expression analysis identified 16 miRNAs differentially modulated in cells subjected to ICD. Integrated miRNA-mRNA functional analysis revealed candidate miRNAs, mRNAs, and modulated pathways associated with Immune System Process (GO Term). In this sense, ICD induced a distinctive transcriptional signature hallmarked by regulation of antigen presentation, a crucial step for a proper immune system antitumor response activation. Interestingly, the major histocompatibility complex class I (MHC-I) pathway was upregulated whereas class II (MHC-II) was downregulated. Analysis of MHC-II associated transcripts and HLA-DR surface expression validated the inhibition of this pathway by ICD on lymphoma cells. miR-4284 and miR-212-3p were the strongest miRNAs upregulated by ICD associated with this event. It is well known that MHC-II expression on tumor cells facilitates the recruitment of CD4+ T cells. However, the interaction between tumor MHC-II and the inhibitory co-receptor LAG-3 on tumor-associated lymphocytes could provide an immunosuppressive signal that directly represses effector cytotoxic activity. In this context, MHC-II downregulation by ICD could enhance antitumor immunity. Overall, we found that the miRNA profile was significantly altered during ICD. Several miRNAs are predicted to be involved in the regulation of Class I and II MHC pathway, whose implication in ICD was demonstrated herein for the first time, which could eventually modulate tumor recognition and attack by the immune system.

Project description:In vertebrates, all cells except circulating blood cells must adhere to support their normal growth and functions. The adherence to extracellular matrix and/or other cells is critical and adherent cells placed in non-adherent conditions either die or form multicellular spheroids. Placing cells in non-adherent conditions has been used to induce differentiation in teratocarcinoma cells and more recently to form organoids . Because of such important consequences induced by cell adhesion on cell growth and function, the transition between adherent and non-adherent states is rather rare. There are however physiological situations, such as blood cells diapedesis, during which cells that circulate into the blood stream must adhere to the endothelial cells and cross the endothelial barrier to reach target tissues. Another example of transition, from an adherent to a non-adherent state, is observed in the metastasic process, where cells detach from the tumor mass and circulate in the blood and lymphatic vasculature prior to reattaching and extravasating to colonize distant organs. The comparative analysis of the only effects of adherence on cellular functions is complicated by the fact that in many study models the acquisition or loss of adherence induces major alterations in cell physiology that would obscure the effects of the adherence itself. For example, P19 teratocarcinoma cells differentiate in suspension spheroids while they do not in adhering conditions. In this context, the comparison between spheroids and adherent cells would not be a comparison between adherent and non-adherent cells, but between differentiated cells adhering between them and undifferentiated cells adhering on plastic. Mouse macrophage cell lines represent one of the rare experimental models that may be suitable to compare the adherent and non-adherent states. Indeed, they grow equally well under adherent and non-adherent conditions and keep their differentiated functions under both conditions. We therefore decided to use this model to analyze the changes between the adherent and the non-adherent state using a broad approach, based on proteomics.

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Integrated mutation, copy number and expression profiling in resectable non-small cell lung cancer

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