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

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.

Call for proposal

FP7-PEOPLE-2013-IEF
See other projects for this call

Coordinator

CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III (F.S.P.)
Address
Calle Melchor Fernandez Almagro 3
28029 Madrid
Spain
Activity type
Research Organisations
EU contribution
€ 230 036,60
Administrative Contact
Luz Mª Garcia (Ms.)