CAVCER

Caveolin-1 integrates stromal mechanical forces chemo-resitance to foster tumor progression

Coordinatore	FUNDACION CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III    more  Organization address address: C/ MELCHOR FERNANDEZ ALMAGRO 3 city: MADRID postcode: 28029 contact info Titolo: Ms. Nome: Luz Mª Cognome: Garcia Email: send email Telefono: +34 914531200 Fax: 34914531245
Nazionalità Coordinatore	Spain [ES]
Totale costo	230˙036 €
EC contributo	230˙036 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2013-IEF
Funding Scheme	MC-IEF
Anno di inizio	2014
Periodo (anno-mese-giorno)	2014-05-01   -   2016-04-30

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	FUNDACION CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III  Organization address address: C/ MELCHOR FERNANDEZ ALMAGRO 3 city: MADRID postcode: 28029 contact info Titolo: Ms. Nome: Luz Mª Cognome: Garcia Email: send email Telefono: +34 914531200 Fax: 34914531245	ES (MADRID)	coordinator	230˙036.60

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 Obiettivo del progetto (Objective)

'Breast cancer affects 1 in 8 women and is the chief cause of female cancer deaths in the EU. Early detection continues to improve survival, but prognosis worsens significantly after metastasis. Metastasis and chemoresistance are linked phenomena, but the molecular basis is unknown. The evidence suggests a role for Caveolin1 (Cav1): i) Cav1 mediates biomechanical remodelling of the extracellular matrix by cancer-associated fibroblasts (CAFs), promoting invasion (host lab publications); ii) Cav1 is involved in drug/radiation resistance, and the Cav1β isoform might regulate resistance of breast tumour cells (TCs) to paclitaxel (literature); iii) The Cav1 content of breast-TC exosomes correlates with metastatic potential (our preliminary data). We propose that acquisition of invasiveness by TCs is related to their release of Cav1-containing exosomes. Cav1-activated CAFs then increase matrix stiffness, providing the appropriate milieu for TC metastasis. The N-terminally curtailed Cav1β precludes chemotherapy-induced tyr14 phosphorylation, preventing Bcl2 binding and conferring resistance. Cav1 α and β might thus balance the interplay between TCs and CAFs during tumour progression. To integrate these data and verify our hypothesis, we propose state-of-the-art approaches and multidisciplinary strategies, ranging from cell biology to animal models and clinical screening studies. As side products, tools of interest will be produced such as a new antibody to Cav1β, useful for stratifying patients according to their likely benefit from paclitaxel therapy, and a new Cav-/- mouse generated by ZFN targeting in the NSG strain, which promises a method for conducting human transplants in genetically modified animal models. The complementary expertise of fellow and host lab, coupled with the excellent scientific environment at the host institute, provide a firm basis for success of this ambitious but sound proposal, thus fostering the fellow’s progress to independence.'