Caveolin-1 integrates stromal mechanical forces chemo-resitance to foster tumor progression
Start date: May 1, 2014,
End date: Apr 30, 2016
Breast cancer affects 1 in 8 women and is the chief cause of female cancerdeaths in the EU. Early detection continues to improve survival, but prognosisworsens significantly after metastasis. Metastasis and chemoresistance are linkedphenomena, but the molecular basis is unknown. The evidence suggests a role forCaveolin1 (Cav1): i) Cav1 mediates biomechanical remodelling of the extracellularmatrix by cancer-associated fibroblasts (CAFs), promoting invasion (host labpublications); ii) Cav1 is involved in drug/radiation resistance, and the Cav1β isoformmight regulate resistance of breast tumour cells (TCs) to paclitaxel (literature); iii)The Cav1 content of breast-TC exosomes correlates with metastatic potential (ourpreliminary data).We propose that acquisition of invasiveness by TCs is related to their releaseof Cav1-containing exosomes. Cav1-activated CAFs then increase matrix stiffness,providing the appropriate milieu for TC metastasis. The N-terminally curtailed Cav1βprecludes chemotherapy-induced tyr14 phosphorylation, preventing Bcl2 binding andconferring resistance. Cav1 α and β might thus balance the interplay between TCsand CAFs during tumour progression.To integrate these data and verify our hypothesis, we propose state-of-the-art approaches andmultidisciplinary strategies, ranging from cell biology to animalmodels and clinical screening studies. As side products, tools of interest will beproduced such as a new antibody to Cav1β, useful for stratifying patients accordingto their likely benefit from paclitaxel therapy, and a new Cav-/- mouse generated byZFN targeting in the NSG strain, which promises a method for conducting humantransplants in genetically modified animal models.The complementary expertise of fellow and host lab, coupled with theexcellent scientific environment at the host institute, provide a firm basis for successof this ambitious but sound proposal, thus fostering the fellow’s progress toindependence.
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