KRASHIMPE
KRas mutation interactions with host immunity in malignant pleural effusion
| Coordinatore | UNIVERSITY OF PATRAS
Spiacenti, non ci sono informazioni su questo coordinatore. Contattare Fabio per maggiori infomrazioni, grazie. |
| Nazionalità Coordinatore | Greece [EL] |
| Totale costo | 1˙995˙000 € |
| EC contributo | 1˙995˙000 € |
| Programma | FP7-IDEAS-ERC
Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) |
| Code Call | ERC-2010-StG_20091118 |
| Funding Scheme | ERC-SG |
| Anno di inizio | 2011 |
| Periodo (anno-mese-giorno) | 2011-04-01 - 2016-03-31 |
Partecipanti
| # | ||||
|---|---|---|---|---|
| 1 |
UNIVERSITY OF PATRAS
Organization address
address: UNIVERSITY CAMPUS RIO PATRAS contact info |
EL (RIO PATRAS) | hostInstitution | 1˙995˙000.00 |
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Obiettivo del progetto (Objective)
'Malignant pleural effusion (MPE) is a significant problem most commonly caused by adenocarcinomas. Although tumors involving the pleura vary in their ability to produce MPE, pathways critical for MPE formation are poorly defined. We have found that mouse tumors harboring mutant (”)KRas produce MPE in mice while tumors without ”KRas do not. LLC and MC38 lung and colon adenocarcinomas, potent inducers of MPE in syngeneic mice, harbor ”KRas that drives constitutive Ras and alternative nuclear factor (NF)-ºB signaling, inflammatory gene expression, and recruitment of specific myeloid cells to the pleural space. In contrast, mouse B16 melanoma and AE17 mesothelioma have wtKRas, lack constitutive Ras/alternative NF-º’ signaling, and are incapable of forming MPE. RNAi-mediated silencing of KRas in MC38 tumors abrogated MPE formation and Ras/alternative NF-º’ activation, while these phenomena were reconstituted in B16 tumors after KRas overexpression. We hypothesize that Ras-activating mutations drive the inflammatory phenotype of adenocarcinomas critical for MPE formation, which is characterized by Ras/alternative NF-ºB activation, inflammatory signalling to host vasculature/immune system, and recruitment of specific myeloid cells, and results in endothelial proliferation/leakiness. To test this hypothesis, we propose to: 1) define the relationship between Ras-activating mutations (RAM) and MPE formation; 2) identify tumor cell Ras-dependent signalling pathways and gene expression signature critical for MPE formation; 3) investigate the host response to tumor cells with RAM that results in MPE; and 4) target Ras and dependent signalling pathways as potential therapy for MPE. Studies will be performed using delivery of mouse/human tumors with/without RAM into the pleura of syngeneic/immunocompromized mice and are likely to yield new insights into the mechanisms of pleural tumor progression and to identify novel approaches to treatment of cancer patients with MPE.'