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HEStaff exchange2023–2027

CHIRON · The role of the non-canonical death receptor signalling in cancer and immune cells

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2023-10-01 → 2027-09-30
EU contribution
€1,531,800
Participants
10
Scheme
HORIZON-TMA-MSCA-SE

Lines connect the coordinator with its partners.

Results in brief

The role of the non-canonical death receptor signalling in cancer and immune cells

Although cancer is still a leading cause of death worldwide, major therapeutic advances have been achieved in the last 15 years. These advances were based on a better understanding of the interaction of tumours and immune cells. The immune system is an essential player as it is highly efficient at eliminating abnormal or potentially cancerous cells. When immune cells recognize aberrant cells they ‘tell’ them to commit suicide, which is mediated by death ligands on the surface of immune cells that bind to death receptors (DRs) on the abnormal cells. Consequently, only tumour cells that learned to avoid destruction by immune cells can become clinically relevant. Many tumours not only learned to ignore the suicidal death signal from immune cells but found even ways to use such signals for their own survival. An important example is the interaction of the death ligand TRAIL with its receptors DR4 and DR5. Many tumour cells can alter this death-signal of TRAIL/DR towards a survival signal that even promotes tumour growth and metastases. The CHIRON project aims to better understand how tumour cells divert the TRAIL/DR-death signal towards a survival signal. This knowledge will be used to develop small molecule inhibitors to block this diversion. By blocking the survival pathway, the tumour cells will become sensitive again towards the TRAIL/DR-induced death signal, offering a novel tool to treat cancers.

Data: CORDIS, © European Union

Project objective

Immune surveillance refers to the ability of the immune system to efficiently induce cell death (apoptosis) in aberrant cells during the early stages of tumour development. This induction of cell death involves the binding of the death ligand TRAIL (TNF-related apoptosis-inducing ligand) to its death receptors (DRs) DR4 and DR5 on the target cell. However, tumour cells can escape this immune surveillance by switching the signalling downstream of DRs from the canonical pro-apoptotic signal towards a survival signal. Previous work from CHIRON partners highlights that this non-canonical DR-signalling regulates both tumour cell behaviour and immune cell functions, demonstrating its central role in understanding the tumour microenvironment. Yet, many aspects of the DR-signalling pathways remain unresolved, hampering the exploitation for diagnostic and therapeutic purposes. CHIRON will address these gaps via its main scientific aims: (i) to develop novel small molecule inhibitors (SMIs) to inhibit non-canonical DR-signalling (WP1), (ii) to identify new DR4- and DR5-binding partners within tumour and immune cells (WP2), and (iii) to gain a mechanistic understanding of the role of the non-canonical DR-signalling pathway in immune cells and cancer types (WP3). To achieve this, the CHIRON consortium combines the multidisciplinary and complementary expertise and resources of six academic and three private sector partners to (i) generate novel knowledge and innovative tools, (ii) strengthen an efficient network of knowledge exchange for further innovative synergies, and (iii) develop the expertise of early-stage and experienced researchers through excellent training. The outputs of the research will (i) develop novel tools to sensitise tumour cells for TRAIL-induced cell death, (ii) guide future diagnostic and therapeutic strategies to utilize and modulate DR-signalling, and (iii) train the expertise necessary to turn such knowledge into innovative services and products.

Original text from CORDIS.

Participants

  • IZMIR BIYOTIP VE GENOM MERKEZI · İzmirCoordinatorTürkiye
  • ANYO LABS AB · GothenburgSweden
  • BUDAPESTI MUSZAKI ES GAZDASAGTUDOMANYI EGYETEM · BudapestHungary
  • COVALAB SAS · BronFrance
  • DOKUZ EYLUL UNIVERSITESI · Alsancak IzmirTürkiye
  • ENIOS APPLICATIONS IDIOTIKI KEFALAIOUCHIKI ETAIREIA · KALLITHEAGreece
  • INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · ParisFrance
  • UNIVERSITAET BERN · BernSwitzerland
  • UNIVERSITE BOURGOGNE EUROPE · DIJONFrance
  • UNIVERSITY OF GALWAY · GalwayIreland

Links

Data: CORDIS, © European Union