NetriCan · Characterization of the role of netrin-1 in the regulation of the Epithelial-to-Mesenchymal Transition during tumor progression.
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-12-01 → 2022-11-30
- EU contribution
- €196,708
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Characterization of the role of netrin-1 in the regulation of the Epithelial-to-Mesenchymal Transition during tumor progression.
In 2020, an estimated 2,68 million new cases were diagnosed and about 1.26 million people died from cancer in Europe (European Cancer Information System). Among all cancer types, 90% of cancer-related deaths, are attributed to the metastatic dissemination of the disease. A specific cellular process called EMT was shown to be necessary to allow tumor cell dissemination to secondary sites and metastatic disease. First identified as an embryonic program, EMT has been shown by many to be reactivated during tumor progression. EMT not only contributes to metastasis, but also to the regulation of tumor cell plasticity by generating stem-like cells with tumor-initiating properties and resistance to conventional therapies. Despite significant improvements for society, in prevention, diagnosis and targeted therapies, it remains a challenge to specifically target the primary tumor mass as well as the disseminated tumor cells that present EMT features. It is now widely accepted that efficient therapies will have to target and/or block the EMT process and allow conventional therapies to efficiently kill cells to treat patients with metastatic tumors. Preliminary in vitro and in vivo results support that inhibition of our target is associated with a shift of the tumor phenotype toward a more epithelial phenotype, potentially more sensitive to regular therapy. The aim of the NetriCan project is to validate the hypothesis that invasive tumor cells turn on the expression of our target as a survival strategy to overcome, and potentially regulate, the stressful EMT program and accomplish the metastatic dissemination cascade. Thus, using our targeted therapy will impact the metastatic disease on two battlefronts: re-epithelializing the primary tumor will increase the efficiency of conventional chemotherapy or immune-checkpoint inhibitors; and preventing the pro-survival role of our target will kill the disseminated tumor cells. The Netrican project demonstrated for the first time a new role for our target in regulating EMT and metastases in tumors, especially for gynaecological tumors such as endometrial cancer.
Data: CORDIS, © European Union
Project objective
Recent data coming from both basic research and clinical trials converge toward the importance of the epithelial/mesenchymal status of a tumor to respond to conventional chemotherapies and immune-checkpoint inhibitors. These observations set the Epithelial-to-Mesenchymal Transition (EMT) program at the centre of cancer biology. Besides its multiple roles in development and during adulthood, EMT is activated during tumor progression not only to allow metastatic dissemination of cancer cells, which is responsible for the vast majority of patients’ death, but also to provide cells with stem-like properties and resistance mechanisms to survive chemotherapy. It is now widely accepted that future therapies will have to target and/or block the EMT process and allow conventional therapies to efficiently kill the differentiated, epithelial cells to treat patients with advanced solid tumors. NetriCan will analyse for the first time the implication of netrin-1 and its dependence receptor UNC5B in the regulation of EMT, either directly or via its cell death-related function. Moreover, the re-epithelialization effect of the anti-netrin-1 monoclonal antibody observed in tumors in vivo and in a preliminary cohort of patients shows that netrin-1/UNC5B may not only be involved in the direct regulation of maintenance of EMT but also serve as a survival mechanism for metastatic tumor cells. To achieve this, Netrican will first analyse how the upregulation of netrin-1 and UNC5B is regulated during EMT. It will then investigate the role of the netrin-1/UNC5B axis in the establishment and maintenance of the EMT program needed for cell dissemination and metastasis. Finally, this project will elucidate the therapeutic potential of the anti-netrin-1 strategy for both triggering primary tumor re-epithelialization and killing mesenchymal tumor cells. In summary, NetriCan will provide innovative findings to develop novel promising therapeutic approach for patients with advanced solid tumors.
Original text from CORDIS.
Participants
- UNIVERSITE LYON 1 CLAUDE BERNARD · Villeurbanne CedexCoordinatorFrance
Links
Data: CORDIS, © European Union