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Mario Pepe



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    P1.03 - Biology (ID 161)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.03-30 - Transcriptome Signatures of Tobacco Carcinogens on Lung Adenocarcinoma Cell Lines (ID 444)

      09:45 - 18:00  |  Presenting Author(s): Mario Pepe

      • Abstract

      Background

      Lung adenocarcinoma (LUAD) sequencing studies and carcinogens induced LUAD in animal models show how different mutational processes leave their specific signatures in the genome. Unluckily those signatures were obtained from heterogeneous tissues containing tumor and stromal cells. Moreover, whole-genome analyses provide a comprehensive collection of genome alterations but tend to lose specificity in the signature that affects the coding region of cancer genomes.

      AIM: To address the importance of mutational signature in the transcriptome of carcinogens induced LUAD cell lines.

      Method

      We investigated the raise of mutations and the changes in the transcriptome profiles of ten different carcinogen-induced LUAD cell lines derived from three different mouse strains and induced with urethane or diethyl-nitrosamine. Data were analyzed for transcripts abundance, sequences alignments, pathways and geneset enrichment, and analyzed the single nucleotide variations (SNV) effect on the three-dimensional structure of proteins and on their functions.

      Result

      The LUAD cells gene expression profiles show classical hallmarks of cancer, where proliferation pathways are up-regulated and adhesion control pathways are down-regulated. Among those altered pathways in LUAD cell lines transcriptome profiles, we observed a clear reprogramming of the metabolism through the up-regulation of the nucleotides synthesis and a contemporary down-regulation of the amino acids synthesis as a switch in the metabolic usage of glucose across the glycolytic pathway. We detected in our LUAD cell lines an average of 10000 SNV. When we focused on the flanking bases of those SNV, we noticed a pure tendency in two specific transitions, A>G and T>C, where the dominant 5´ flanking nucleotide is C and the dominant 3´ is G. We investigated the distribution of common SNV across the chromosomes to highlight mutational hotspots. In Kras-mutant LUAD cell lines, we observed that both carcinogens tend to leave their specific mutational fingerprints with a major density in the terminal regions of the chromosomes. When we compared the specific genomic position of every induced SNV and correlated it with the different levels of heterogeneity in LUAD cell lines, we observed in all of them 15 common SNV in 11 different genes. Among those genes, we pinned two key genes of the glycolytic pathway: G6pd2 and Aldort1.

      Conclusion

      From the tobacco carcinogens transcriptome signatures of LUAD cells, we propose here an uncharted role of two altered forms of G6pd2 and Aldort1. Their corresponding proteins: G6PD2 and ALDOA, are able to drive the glucose usage toward the nucleotide synthesis, resulting in an enhancement of the tumor cells proliferation and in the LUAD pathogenicity. We believe that those two proteins could be more investigated as novel pharmacological targets for human LUAD treatment

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-48 - Tumor-Derived Granulocyte Chemotactic Protein 2 Cooperates with Proteases to Drive Lung Adenocarcinoma (ID 1326)

      10:15 - 18:15  |  Author(s): Mario Pepe

      • Abstract

      Background

      Introduction: Lung adenocarcinoma (LADC) commonly arises in the lungs of smokers that are heavily affected by chronic inflammation. Inflammatory signaling from tumor to host cells is critically involved in the pathogenesis of LADC, but the exact mechanisms by which the lung epithelium interacts with the immune system during carcinogenesis are obscure.

      Objectives: We discovered that murine and human LADC cell lines overexpress the inflammatory and angiogenic CXC chemokine granulocyte chemotactic protein 2 (GCP2, CXCL6) compared with normal epithelial cells. GCP2 is processed by immune proteases: neutrophil elastase (NE, ELANE), proteinase 3 (PR3, PRTN3) and matrix metalloproteinase 9 (MMP9, MMP9). We suppose that GCP2 interacts with these proteases to drive LADC and aimed at investigating its function(s).

      Method

      GCP2, MMP9 and PR3 expressions were determined by ELISA and immunohistochemistry. Mouse and human microarray data were analyzed using Affymetrix Transcriptome Analysis Console. GCP2 silencing using dedicated shRNA pools (SantaCruz Biotechnology) and NE/PR3 or MMP9 compound knockout mice were used to study GCP2 interaction with immune proteases in LADC progression.

      Result

      Murine and human LADC tumors and cell lines overexpress GCP2, MMP9, NE and PR3 at the mRNA and protein levels. GCP2 is sequestered to tumor cells, whereas proteases are produced by tumor-infiltrating immune cells. LADC-secreted GCP2 is incompletely processed and require MMP9, NE or PR3 for full activation and vasoactive effects. Moreover, GCP2-silenced LADC cells injected in mice show a lack in metastasis formation.

      Conclusion

      Our results indicate that tumor-originated GCP2 cooperates with immune proteases to drive LADC, providing a paradigm of how the respiratory epithelium coopts the innate immune system during carcinogenesis.