Project data

Funding Entity: Italian Ministry of University and Research

Call: PRIN 2020

Coordinator: Università degli Studi di VERONA

UNISI Principal Investigator: Maria Grazia Castagna

Department: Medicine, surgery and neuroscience

Start date: 22 March 2022 – End date: 22 March 2025

 

Project description

Cancer is the second cause of death worldwide, constituting a crucial medical and socio-economic challenge. Gene/environment interactions play a pivotal role in the development of cancer.
Environmental pollutants, several of which act as endocrine disruptors (EDs), and potentially modifiable  metabolic and lifestyle factors (e.g. obesity, high fat diet, and lack of physical activity) may interact with
genetic background to increase the risk and modulate aggressiveness of many different cancers, including endocrine-related breast (BC) and thyroid (TC) cancers.
This project aims at dissecting the complex interplay between BC/TC genomic landscape, exposure to EDs, and metabolic/lifestyle factors by:
1. Retrospectively and prospectively correlating EDs exposure, obesity/body composition, nutritional and physical activity habits with the genomic landscape (using NGS-based, targeted genomic profiling) of
BC and TC patients (WP1 and WP2);
2. Defining the molecular mechanisms of action of selected EDs and nutrients in genetically defined preclinical models of BC/TC in vitro (WP3);
3. Understanding the role of EDs, dietary factors, and physical activity in tumor development and progression in vivo employing genetically engineered mouse models (GEMM) of BC/TC (WP4);
4. Preliminarily testing biological changes induced by a structured lifestyle intervention centered on nutritional counseling and adapted physical exercise on selected cohorts of BC and TC (WP5).
The overall aim of the project is to identify driver mechanisms/molecular mediators through which EDs and metabolic/lifestyle factors exert their tumor-promoting activity; potentially actionable genetic
alterations/signaling pathways could be then exploited to develop targeted prevention/treatment strategies using pharmacological and/or lifestyle intervention approaches, aimed at reversing such
tumor-promoting effects. The proposed  experimental strategies aim at validating potential candidates identified by literature and our preliminary data (e.g. MAPK/PI3K pathway activation, HSP90 expression), on one hand, and discovery-based  identification of new potential candidates, using integrated omics-based approaches in preclinical models in vitro and in vivo, on the other. Finally, while patients’ cohorts will investigate clinically evident tumors, in which neoplastic transformation and variable degrees of progression have already occurred, in vitro models and GEMM will recapitulate the entire process from pre-neoplastic changes to overt tumor progression, potentially allowing for translation of the results achieved in a preventive setting.
Altogether, this project will propose several innovations, by linking external sources of exposure to biomarkers, disease phenotypes, and potential molecular targets, which could be widely exploited in
diagnostic, therapeutic, preventive and health-economic applications.

 

This project has received funding from the Italian Ministry of University and Research PRIN programme