„The role of ferroptotic tumor cells in tumor development by modifying the tumor microenvironment” GRANT NCN SONATA

grant no: 2019/35/D/NZ5/03058

Head: Paulina Kucharzewska-Siembieda

Cancer is one of the leading causes of death in developed countries. For a long time, tumors were thought to be made up of only cancer cells, but research has shown that they live surrounded by other cells, such as fibroblasts, cells of the immune system and endothelial cells of blood vessels, which together form the tumor microenvironment. Cancer cells reprogram the microenvironment cells to promote tumor growth and invasion. Therefore, understanding the interaction between the microenvironment and cancer cells is crucial for the development of new treatments.

Hypoxia and nutrient depletion, which are inherent stress factors of the tumor microenvironment, are the result of insufficient blood supply in a rapidly growing tumor, as well as the effect of anti-cancer therapies. Cancer cells respond to the cytotoxic effects of these stress factors either by activating the adaptive processes that enable them to survive, or on the contrary, by cell death. Cell death mainly occurs by necrosis as apoptosis is limited in tumor cells. In contrast to apoptotic cell death, which suppresses tumor development, necrosis may paradoxically promote tumor growth and progression. Therefore, the appearance of a necrotic core in many types of tumors is associated with a poor prognosis in patients. For many years, necrosis was considered an accidental and genetically unprogrammed form of cell death. However, it is now known that there are many types of cell death distinct from apoptosis, which are controlled by specific genetic mechanisms and which morphologically resemble necrosis, such as oncosis, necroptosis and ferroptosis. 

In my research, I plan to focus on ferroptosis and its role in cancer development. Ferroptosis is cell death caused by excessive oxidation of cell membrane lipids in an iron-dependent process due to oxidative stress. The role of ferroptosis in tumor development remains unclear. Based on previous research, ferroptosis contributes to the inhibition of tumor growth, and interestingly, invasive cancer cells, cancer stem cells and chemotherapy-resistant cancer cells are particularly susceptible to ferroptosis. Thus, the induction of ferroptosis in cancerous tumors seems to be an interesting strategy for anticancer therapies. On the other hand, cancer cells that die as a result of ferroptosis secrete numerous molecules into the extracellular space that may potentially have a tumor-promoting effect by modulating the immune system cells, inducing angiogenesis, and activating tumor cells. Therefore, we suspect that ferroptosis induced, e.g. as a result of anti-cancer therapies, may potentially support the development of cancer and contribute to cancer recurrence by modifying the tumor microenvironment. 

Furthermore, we believe that tumor hypoxia may play an important role in this phenomenon as it induces the expression of some secreted molecules. Therefore, we believe that it is necessary to study the effect of ferroptotic tumor cells on the tumor microenvironment and to identify the molecular mechanisms of these interactions. In our project, we will perform a series of experiments and analyzes that will verify our hypothesis. These will be experiments conducted using both in vitro cell cultures and animal models. We are convinced that the new knowledge gained during the implementation of this project will not only contribute to a deeper understanding of the biology of cancer, but also in the future may lead to the development of more effective anti-cancer therapies.