Mechanobiology of cancer progression

Introduction

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 and Tumour Vascular Network

Fibrotic stiffening is caused by fibroblast 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.

Project Goals

To advance the field, I will develop a revolutionary platform able to recapitulate tumour fibrosis by exploiting the vascularisation of a living organism.

Methodology

To achieve my goal, I will use human breast cancer cells adhering to 3D polymeric micro scaffolds to create arrays of tumour microenvironments. I will implant the arrays in vivo in the chorioallantoic membrane of an embryonated avian egg to elicit a foreign-body fibrotic reaction.

Scaffold Geometry Variation

I will vary the micro scaffolds' geometry to condition tumour infiltration by the host’s vessels and cells.

Imaging and Analysis

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.

Computational Modelling

I will predict mass transport of solutes and anticancer agents by computational modelling.

Validation

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.

Interdisciplinary Approach

This project combines mechanobiology with bioengineering, biomechanics, oncology, genetics, microtechnology, intravital imaging, biophysics, and pharmacology to understand the progression mechanisms of the most incurable cancers.

Ethical and Standardizable Testing

It will also provide an ethical and standardizable testing platform to boost the clinical translation of new therapeutic products in oncology.