Investigating the effects of cGAS-STING-dependent innate immune responses in BRCA2-deficient cells
<p>Tumours with BRCA2 gene deficiency, retain the ability to proliferate, despite the genomic instability resulting from DNA damage accumulation. These tumours can be targeted with Poly-ADP ribose polymerase inhibitors (PARPi), which increase the susceptibility of BRCA2-mutated tumours to DNA...
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2022
|
| Subjects: |
| _version_ | 1826309037641170944 |
|---|---|
| author | Trajanovska, T |
| author2 | Tarsounas, M |
| author_facet | Tarsounas, M Trajanovska, T |
| author_sort | Trajanovska, T |
| collection | OXFORD |
| description | <p>Tumours with BRCA2 gene deficiency, retain the ability to proliferate, despite the genomic instability resulting from DNA damage accumulation. These tumours can be targeted with Poly-ADP ribose polymerase inhibitors (PARPi), which increase the susceptibility of BRCA2-mutated tumours to DNA damaging agents. However, in spite of the therapeutic benefits and low toxicity in patients, PARPi resistance remains a clinical challenge. Therefore, improved approaches for targeting BRCA2-mutated tumours are being sought to improve patient outcomes. Previously, BRCA2 depletion was shown to activate the cGAS-STING-dependent innate immune responses which have the potential to promote antitumour immunity. In this project, we set out to investigate the effects of stimulating the cGAS-STING-dependent innate immune responses using the STING agonist DMXAA in two BRCA2-deficient cell models. DMXAA treatment activated the cGAS-STING signalling pathway in only one of the BRCA2-deficient cell models, characterised by an increase in IRF3 phosphorylation, but this did not lead to an increase in DNA damage. PARPi treatment is known to activate the cGAS-STING signalling pathway and induce DNA damage in BRCA2-deficient cells. Therefore, we co-treated BRCA2-deficient cells with the PARPi Talazoparib and DMXAA in order to activate STING mediated innate immune responses and increase DNA damage. The combination treatment led to activation of cGAS-STING signalling, upregulation of interferon-stimulated genes and an increase in DNA damage in both cell models. Finally, we investigated the effect of combining DMXXA and Talazoparib on the viability of BRCA2-deficient cells. However, DMXAA did not lead to increased sensitivity of the BRCA2-deficient cells to Talazoparib. Whilst these are preliminary results, they suggest that the effect of STING agonists may vary depending on cell type and they may not have the predicted efficacy in BRCA2-deficient cells. </p> |
| first_indexed | 2024-03-07T07:28:15Z |
| format | Thesis |
| id | oxford-uuid:fe684cca-9e79-464d-bf08-ca00dd75d4f3 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:28:15Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | oxford-uuid:fe684cca-9e79-464d-bf08-ca00dd75d4f32022-11-30T10:43:26ZInvestigating the effects of cGAS-STING-dependent innate immune responses in BRCA2-deficient cells Thesishttp://purl.org/coar/resource_type/c_bdccuuid:fe684cca-9e79-464d-bf08-ca00dd75d4f3Genomic Instability and TumourigenesisEnglishHyrax Deposit2022Trajanovska, TTarsounas, M<p>Tumours with BRCA2 gene deficiency, retain the ability to proliferate, despite the genomic instability resulting from DNA damage accumulation. These tumours can be targeted with Poly-ADP ribose polymerase inhibitors (PARPi), which increase the susceptibility of BRCA2-mutated tumours to DNA damaging agents. However, in spite of the therapeutic benefits and low toxicity in patients, PARPi resistance remains a clinical challenge. Therefore, improved approaches for targeting BRCA2-mutated tumours are being sought to improve patient outcomes. Previously, BRCA2 depletion was shown to activate the cGAS-STING-dependent innate immune responses which have the potential to promote antitumour immunity. In this project, we set out to investigate the effects of stimulating the cGAS-STING-dependent innate immune responses using the STING agonist DMXAA in two BRCA2-deficient cell models. DMXAA treatment activated the cGAS-STING signalling pathway in only one of the BRCA2-deficient cell models, characterised by an increase in IRF3 phosphorylation, but this did not lead to an increase in DNA damage. PARPi treatment is known to activate the cGAS-STING signalling pathway and induce DNA damage in BRCA2-deficient cells. Therefore, we co-treated BRCA2-deficient cells with the PARPi Talazoparib and DMXAA in order to activate STING mediated innate immune responses and increase DNA damage. The combination treatment led to activation of cGAS-STING signalling, upregulation of interferon-stimulated genes and an increase in DNA damage in both cell models. Finally, we investigated the effect of combining DMXXA and Talazoparib on the viability of BRCA2-deficient cells. However, DMXAA did not lead to increased sensitivity of the BRCA2-deficient cells to Talazoparib. Whilst these are preliminary results, they suggest that the effect of STING agonists may vary depending on cell type and they may not have the predicted efficacy in BRCA2-deficient cells. </p> |
| spellingShingle | Genomic Instability and Tumourigenesis Trajanovska, T Investigating the effects of cGAS-STING-dependent innate immune responses in BRCA2-deficient cells |
| title | Investigating the effects of cGAS-STING-dependent innate immune responses in BRCA2-deficient cells
|
| title_full | Investigating the effects of cGAS-STING-dependent innate immune responses in BRCA2-deficient cells
|
| title_fullStr | Investigating the effects of cGAS-STING-dependent innate immune responses in BRCA2-deficient cells
|
| title_full_unstemmed | Investigating the effects of cGAS-STING-dependent innate immune responses in BRCA2-deficient cells
|
| title_short | Investigating the effects of cGAS-STING-dependent innate immune responses in BRCA2-deficient cells
|
| title_sort | investigating the effects of cgas sting dependent innate immune responses in brca2 deficient cells |
| topic | Genomic Instability and Tumourigenesis |
| work_keys_str_mv | AT trajanovskat investigatingtheeffectsofcgasstingdependentinnateimmuneresponsesinbrca2deficientcells |