Mechanobiology of cancer progression

Descripción del proyecto

Un modelo innovador de fibrosis tumoral

Las células cancerosas existen en un microentorno complejo compuesto por la matriz extracelular (MEC), células vasculares, estromales e inmunitarias. Pruebas recientes indican que la remodelación de la MEC provoca fibrosis y rigidez tumoral, cuyo grado está asociado a la agresividad del tumor y a la resistencia al tratamiento. El objetivo del proyecto BEACONSANDEGG, financiado por el Consejo Europeo de Investigación, es elaborar un modelo de evolución del cáncer de mama que reproduzca la fibrosis y la vascularización del tumor. Los investigadores emplearán una matriz polimérica con células cancerosas para recrear el microambiente tumoral humano «in vitro» e implantarlo «in vivo» en un embrión de ave para provocar la fibrosis. El proyecto proporcionará información sin precedentes sobre los mecanismos de la fibrosis tumoral y su repercusión en la eficacia de los agentes terapéuticos.

Objetivo

Invasive cancers are a leading cause of death worldwide, with almost ten million deaths per year caused by resistance to antitumor treatments. In breast cancer, aggressiveness correlates with fibrotic stiffening of the tumour. There is an urgent need to understand how the fibrotic microenvironment evolves, to design better targeted cancer therapies. Fibrotic stiffening is caused by fibroblasts secretion of a matrix with mechanical properties that stabilise the tumour vascular network. However, the hierarchy and stability of the tumour vascular network are not reproducible in vitro. To advance the field, I will develop a revolutionary platform able to recapitulate tumour fibrosis by exploiting the vascularisation of a living organism.
To achieve my goal, I will use human breast cancer cells adhering to 3D polymeric micro scaffolds to create arrays of tumour micro environments. I will implant the arrays in vivo in the chorioallantoic membrane of an embryonated avian egg, to elicit a foreign-body fibrotic reaction. I will vary the micro scaffolds geometry to condition tumour infiltration by the hosts vessels and cells. I will exploit fluorescent spatial beacons incorporated in the micro scaffolds for multiphoton image correlation, to derive morphological and functional information of the regenerated fibrous matrix and vessels. I will predict mass transport of solutes and anticancer agents by computational modelling. To validate the platform, I will quantify in vivo the dose-dependent efficacy and cancer specificity of therapeutic agents whose success is known to depend on the fibrotic stage of tumours.
This project combines mechanobiology to bioengineering, biomechanics, oncology, genetics, microtechnology, intravital imaging, biophysics and pharmacology to understand the progression mechanisms of the most incurable cancers. It will also provide an ethical and standardizable testing platform to boost the clinical translation of new therapeutic products in oncology.