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Molecular basis of the cross-talk between chronic inflammation and cancer

Periodic Reporting for period 4 - CrIC (Molecular basis of the cross-talk between chronic inflammation and cancer)

Reporting period: 2019-10-01 to 2021-03-31

Chronic inflammation is associated with a broad range of etiologically distinct human pathologies, including cancer, auto-inflammatory and auto-immune diseases. In addition, chronic inflammation also feeds several disease-associated comorbidities, such as metabolic dysfunctions. Therefore, understanding the molecular mechanisms through which chronic pathological inflammation is triggered and maintained is crucial to the development of targeted therapies.
The CrIC project aimed at identifying the molecular mechanisms at play in the onset and maintenance of tumor promoting inflammation. Particular interest was brought to inflammation associated with the accumulation of cytosolic nucleic acid species. The latter include ssDNA, dsDNA and RNA:DNA hybrids, that can derive from pathogen infections (viruses, bacteria), but also originate from mitochondria or the nucleus. In recent years several pathways have been identified as involved in the detection of aberrant cytosolic nucleic acid species. In particular the cGAS receptor has been established as one of the key detectors of these moieties and as a potent inducer of type I Interferon responses. Upon detection of cytosolic nucleic acids, cGAS produces the cGAMP second messenger that can interact with the STIGN adaptor protein, leading to the assembly of a STING signalosome that orchestrates tpe I Interferon responses.
In recent years, , it has become apparent that signaling output in the presence of pathological nucleic acid species is dictated by several layers of regulations including the diversity of nucleic acid substrates that coexist in cells and a vast array of potential receptors. Furthermore, despite chronic inflammation being associated with several human pathologies, the range of symptoms experienced by patients varies depending on parameters that are yet to be determined.
The aim of the CrIC project was to provide insight into the molecular mechanisms involved in the initiation and maintenance of nucleic acid-associated chronic inflammation, in order to assess how they contribute to pathological outcomes.
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/)). 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.
Therefore, the CrIC project has provided insight into the molecular mechanisms that contribute to pathological inflammation in the presence of cytosolic nucleic acid species. In particular work performed through CrIC has helped establish that inflammatory pathways are intertwined with metabolic pathways. It revealed that agonists of STING can directly activate metabolic pathways, thereby promoting gross metabolic alterations. These metabolic side-effects of STIGN activation are crucial to take into consideration while designing therapeutic approaches that aim to activate STING. This is therefore critical to consider in STING targeting immunotherapies. Altogether, by uncovering the complexity of the interconnexion between the pathways engaged in detection of pathological nucleic acids and metabolic pathways, CrIC revealed how modulating chronic pathological inflammation has far reaching impacts on global health.
Main CrIC achievements