The application of chemotherapy or radiotherapy for anaplastic cancers is often associated with disease progression and frequent relapse, indicating the importance of communication between dying and living cells. Thus, the basic strategy to maintain homeostasis in healthy tissue becomes a powerful intrinsic force of tumor repopulation in response to spontaneous or therapy-promoted cell death. Although cell death was believed for years to mediate tumor suppression, a growing body of data points to a paradoxical relationship between the presence of dying cells in tumor tissue and poor disease outcome. The core of this paradox lies in the fact that dying cells, generated either spontaneously or by therapy, are the main booster for cell division and the main source of signals involved in tumor repopulation and therapy failure. The direct link between inflammation and proliferative burst triggered by dying cells was verified through the “Phoenix rising” pathway" and the prominent role of prostaglandin E2 (PGE2) in the transmission of mitogen signals to neighboring cells. All this qualifies advanced colorectal carcinoma as an inflammation driven tumor prototype making it an excellent platform for the screening of drugs that can block the ”Phoenix rising“ pathway.

ADVANCED intends to upgrade basic knowledge of the cell death-triggered tumor repopulation in high-grade colorectal cancer, as a prototype of an inflammation-driven tumor, and to explore the therapeutic potential of new anti-inflammatory drugs belonging to inhibitors of cyclooxygenase-2 (COX-2) and lipoxygenases (LOX), as well as hybrid molecules of chemotherapeutic and anti-inflammatory drugs. We strive to develop a new tumor repopulation model through the establishment of mouse-derived organoids (MDOs). The molecular pattern of tumor repopulation will be defined by transcriptional profiling, while selected drugs will be screened starting from the novel MDOs and syngeneic in vivo models, and ending with colorectal cancer patient-derived organoids (PDOs). The results of this project will help development of strategies for high-grade colorectal cancer treatment by preventing inflammation-driven repopulation.