Persistent DNA strand breaks induce a CAF-like phenotype in normal fibroblasts
Cancer-associated fibroblasts (CAFs) are an emerging target for cancer therapy as they promote tumour growth and metastatic potential. However, CAF targeting is complicated by the lack of knowledge-based strategies aiming to selectively eliminate these cells. There is a growing body of evidence sugg...
| Egile Nagusiak: | , , , , , , , , , |
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| Formatua: | Journal article |
| Hizkuntza: | English |
| Argitaratua: |
Impact Journals
2018
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| _version_ | 1826286613503672320 |
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| author | Legrand, A Poletto, M Pankova, D Clementi, E Moore, J Castro-Giner, F Ryan, A O'Neill, E Markkanen, E Dianov, G |
| author_facet | Legrand, A Poletto, M Pankova, D Clementi, E Moore, J Castro-Giner, F Ryan, A O'Neill, E Markkanen, E Dianov, G |
| author_sort | Legrand, A |
| collection | OXFORD |
| description | Cancer-associated fibroblasts (CAFs) are an emerging target for cancer therapy as they promote tumour growth and metastatic potential. However, CAF targeting is complicated by the lack of knowledge-based strategies aiming to selectively eliminate these cells. There is a growing body of evidence suggesting that a pro-inflammatory microenvironment (e.g. ROS and cytokines) promotes CAF formation during tumorigenesis, although the exact mechanisms involved remain unclear. In this study, we reveal that a prolonged pro-inflammatory stimulation causes a de facto deficiency in base excision repair, generating unrepaired DNA strand breaks and thereby triggering an ATF4-dependent reprogramming of normal fibroblasts into CAF-like cells. Based on the phenotype of in vitro-generated CAFs, we demonstrate that midostaurin, a clinically relevant compound, selectively eliminates CAF-like cells deficient in base excision repair and prevents their stimulatory role in cancer cell growth and migration. |
| first_indexed | 2024-03-07T01:46:20Z |
| format | Journal article |
| id | oxford-uuid:988db129-c0cd-41c9-b9bc-2a326d1c2f65 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:46:20Z |
| publishDate | 2018 |
| publisher | Impact Journals |
| record_format | dspace |
| spelling | oxford-uuid:988db129-c0cd-41c9-b9bc-2a326d1c2f652022-03-27T00:07:46ZPersistent DNA strand breaks induce a CAF-like phenotype in normal fibroblastsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:988db129-c0cd-41c9-b9bc-2a326d1c2f65EnglishSymplectic Elements at OxfordImpact Journals2018Legrand, APoletto, MPankova, DClementi, EMoore, JCastro-Giner, FRyan, AO'Neill, EMarkkanen, EDianov, GCancer-associated fibroblasts (CAFs) are an emerging target for cancer therapy as they promote tumour growth and metastatic potential. However, CAF targeting is complicated by the lack of knowledge-based strategies aiming to selectively eliminate these cells. There is a growing body of evidence suggesting that a pro-inflammatory microenvironment (e.g. ROS and cytokines) promotes CAF formation during tumorigenesis, although the exact mechanisms involved remain unclear. In this study, we reveal that a prolonged pro-inflammatory stimulation causes a de facto deficiency in base excision repair, generating unrepaired DNA strand breaks and thereby triggering an ATF4-dependent reprogramming of normal fibroblasts into CAF-like cells. Based on the phenotype of in vitro-generated CAFs, we demonstrate that midostaurin, a clinically relevant compound, selectively eliminates CAF-like cells deficient in base excision repair and prevents their stimulatory role in cancer cell growth and migration. |
| spellingShingle | Legrand, A Poletto, M Pankova, D Clementi, E Moore, J Castro-Giner, F Ryan, A O'Neill, E Markkanen, E Dianov, G Persistent DNA strand breaks induce a CAF-like phenotype in normal fibroblasts |
| title | Persistent DNA strand breaks induce a CAF-like phenotype in normal fibroblasts |
| title_full | Persistent DNA strand breaks induce a CAF-like phenotype in normal fibroblasts |
| title_fullStr | Persistent DNA strand breaks induce a CAF-like phenotype in normal fibroblasts |
| title_full_unstemmed | Persistent DNA strand breaks induce a CAF-like phenotype in normal fibroblasts |
| title_short | Persistent DNA strand breaks induce a CAF-like phenotype in normal fibroblasts |
| title_sort | persistent dna strand breaks induce a caf like phenotype in normal fibroblasts |
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