Research Celine Civati

Abstract

Heart failure (HF) and cancer are the two most common causes of death. An increasing number of patients suffer from both diseases. In the past, their occurrence in the same patients was exclusively attributed to shared risk factors, e.g. smoking. Recent studies have demonstrated that HF directly stimulates cancer growth in different mouse models of HF and cancer, but the underlying mechanisms are incompletely understood. An important unanswered question is whether treating HF with available therapy affect cancer progression. First, I will test the effects of currently used HF treatments in a mouse model of HF and solid cancer. I expect that specific HF therapies will slow HF-enhanced cancer growth. Second, I will test the same treatments in a mouse model of HF and spontaneously metastatic cancer. The comparison of the effects of HF treatments on solid and metastatic tumors will help to test the central hypothesis; it will provide clinicians with useful insights to select therapies for their patients, but will also be relevant to individuate the pathways involved in HF-enhanced cancer growth. Third, I will perform single-nuclei RNA sequencing of both tumors and myocardium. These experiments will reveal the underlying mechanisms linking HF to cancer thanks to the identification of receptors present on both tissues. The ultimate goal would be the identification of novel therapeutic targets, potentially helping millions of patients.

Researcher(s)

• Promoter: Segers Vincent
• Co-promoter: De Keulenaer Gilles
• Co-promoter: Van Laere Steven
• Fellow: Civati Celine

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Recent clinical studies indicate that patients with heart failure develop cancer more frequently than patients of the same age without heart failure, indicating that heart failure could induce cancer growth. Recent experiments in animals confirmed that mice with heart failure develop more aggressive forms colon or breast cancer than mice without heart failure. The mechanisms underlying these exciting discoveries have not been determined, yet. Research into these mechanisms, however, is highly relevant, because it could provide novel insights in the pathophysiology of both disorders. The central hypothesis of the current project is that neuregulin-1 (NRG1) links heart failure to cancer. NRG1 is a endothelial-derived growth factor that is produced during heart failure and that has cardioprotective properties. NRG1 is the natural ligand of ERBB receptors—ERBB2, ERBB3, and ERBB4—which are expressed at different levels in cancer cells, and which are known as oncogenes. Blocking antibodies against ERBB2 and ERBB3 are currently used as anti-cancer drugs. We will test this hypothesis in mouse models of colorectal and breast cancer. Heart failure will be induced by ligation of a coronary artery, inducing a myocardial infarction. The role of NRG1 will be evaluated with transgenic knockout technology. We will also test the cardioprotective and pro-carcinogenic effects of administered NRG1 and specific ERBB4 agonists in these mouse models. NRG1 and ERBB4 agonists are in development for the treatment of heart failure. This project is scientifically and clinically novel for a number of reasons: it links pathophysiology of cancer to the pathophysiology of heart failure and circulatory failure. It is also important for the development of novel ERBB-based drugs for the treatment of heart failure. It will help in differentiating the growth stimulating effects of NRG1 or specific ERBB4 agonists, regardless of their cardioprotective properties.

Researcher(s)

• Promoter: Segers Vincent
• Fellow: Civati Celine

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project