Until recently, it was believed that cancer was only driven by changes inside cells: genes become mutated, cells grow uncontrolled, and a tumour arises. However, recent evidence indicates that the surrounding environment where tumour cells live also plays an important role in cancer. Susceptibility factors, different from the mutations, might also influence cancer progression. This project aims at understanding how the tumour cells interact with the specialised environment where these cells reside, and how we can target these interactions to improve patient care.
In a group of bone marrow disorders known as myeloproliferative neoplasms, a defective gene causes hematopoietic stem cells (HSCs) to make too many blood cells. This increases the risk of formation of blood clots, leading to increased rates of cardiovascular diseases and stroke. As the blood cells build up, the disease worsens, sometimes causing tissue degeneration in the form of myelofibrosis or even evolving into cancer. Myelofibrosis is a serious condition that disrupts the normal production of blood cells. The only real cure is a bone marrow transplant, but this is not feasible in many patients due to the toxicity of this procedure in these patients. Therefore, these diseases are generally not cured, they increase in the elderly and represent a large socio-economical burden.
Studying the process in mice, our team discovered that the mutant HSCs produced an abundance of small inflammatory proteins called cytokines that were damaging nearby neurons. This damage, in turn, prevented the nerves from activating other cells that help regulate HSCs. This damage increased the potential for myeloproliferative neoplasms. When we added an analog of the neurotransmitter adrenaline to compensate for the damaged neurons’ inability to fire, we observed tissue regeneration and improvement of myelofibrosis. Similar results have been observed in a phase II clinical study performed in collaboration with the Swiss Cancer Group.
To be able to treat this damage to neighbouring cells we first need to understand how these neighbours interact with normal and mutated HSCs. Therefore, one first goal of this project is aimed at understanding how this partnership of HSCs and their neighbouring cells is established and to identify pathways that regulate these interactions. A second goal is to study niche alteraltions in myeloproliferative diseases and manipulate these pathways for therapeutic purposes. A third goal exploits another potential susceptibility factor that might influence myeloproliferative disease progression: HSC regulation by sex hormones. Overall, these aims will increase our knowledge of the regulation of the HSC niche and how to target it therapeutically.
