Completion of the objectives set within the proposal has led to:
- insight into ways in which inflammation is initiated within tumor cells. Indeed, we have shown that mobile genetic elements are a source of pathological nucleic acids that are recognized by cGAS to promote chronic type I Interferon production. Indeed, absence of efficient DNA repair through the Fanconi Anemia DNA repair pathway or chemotherapy regimens both lead to de-repression of mobile genetic elements, in particular of the LINE-1 family, that trigger type I Interferon responses (Bregnard et al, EBioMedicine, 2016).
- we have shown that cGAS-STING activation is controlled by the Lysyl tRNA synthetase (LysRS). We have shown that LysRS interacts with RNA:DNA hybrids, preventing their detection by cGAS, but also produces a second messenger (diadenosine tetraphosphate – Ap4A) that interacts with STING, preventing its association with cGAMP. This control of the cGAS-STING axis, is central to determining the amplitude and duration of type I Interferon responses (Guerra et al, Science Adv; Patent : PCT : WO2021043992). The impact of the identified pathway on tumorigenesis is currently under characterization in the laboratory.
- We have shown that the activation of the cGAS-STING pathway is also controlled by DNA repair proteins, opening novel perspectives in our understanding of how DNA repair and inflammatory pathways contribute to pervasive cancer-associated inflammation (Taffoni et al, Frontiers in Immunology, in press; Taffoni, Marines et al, manuscript in preparation).
- Finally, we demonstrate that STING, independently of its role in inflammatory responses, controls metabolic homeostasis. In particular, we show that STING regulates polyunsaturated fatty acid (PUFAs) metabolism directly, through interacting with the Fatty acid desaturase 2 enzyme and inhibiting its activity. Furthermore, we show that PUFAs exert a negative control of STING activity (Vila et al, bioRXiv).
Work performed within the scope of CrIC has also allowed us to establish strong collaborations with several international team, allowing us to establish an interdisciplinary research network (
https://frontinov.cnrs.fr/)(odnośnik otworzy się w nowym oknie)). Finally, work stemming from CrIC has allowed us to benefit from an ERC-Proof-of Concept Grant (‘Decreasing Pancreatic Adenocarcinoma-related Inflammation using small molecule inhibitors of STING’ - DIM-CrIC ; GA #893772)
• Patent: STING inhibitors and their therapeutic uses. PCT : WO2021043992.
