Formation of an invasion-permissive matrix requires TGFβ/SNAIL1-regulated alternative splicing of fibronectin
© 2023. The Author(s)..
BACKGROUND: As in most solid cancers, the emergence of cells with oncogenic mutations in the mammary epithelium alters the tissue homeostasis. Some soluble factors, such as TGFβ, potently modify the behavior of healthy stromal cells. A subpopulation of cancer-associated fibroblasts expressing a TGFβ target, the SNAIL1 transcription factor, display myofibroblastic abilities that rearrange the stromal architecture. Breast tumors with the presence of SNAIL1 in the stromal compartment, and with aligned extracellular fiber, are associated with poor survival prognoses.
METHODS: We used deep RNA sequencing and biochemical techniques to study alternative splicing and human tumor databases to test for associations (correlation t-test) between SNAIL1 and fibronectin isoforms. Three-dimensional extracellular matrices generated from fibroblasts were used to study the mechanical properties and actions of the extracellular matrices on tumor cell and fibroblast behaviors. A metastatic mouse model of breast cancer was used to test the action of fibronectin isoforms on lung metastasis.
RESULTS: In silico studies showed that SNAIL1 correlates with the expression of the extra domain A (EDA)-containing (EDA+) fibronectin in advanced human breast cancer and other types of epithelial cancers. In TGFβ-activated fibroblasts, alternative splicing of fibronectin as well as of 500 other genes was modified by eliminating SNAIL1. Biochemical analyses demonstrated that SNAIL1 favors the inclusion of the EDA exon by modulating the activity of the SRSF1 splicing factor. Similar to Snai1 knockout fibroblasts, EDA- fibronectin fibroblasts produce an extracellular matrix that does not sustain TGFβ-induced fiber organization, rigidity, fibroblast activation, or tumor cell invasion. The presence of EDA+ fibronectin changes the action of metalloproteinases on fibronectin fibers. Critically, in an mouse orthotopic breast cancer model, the absence of the fibronectin EDA domain completely prevents lung metastasis.
CONCLUSIONS: Our results support the requirement of EDA+ fibronectin in the generation of a metastasis permissive stromal architecture in breast cancers and its molecular control by SNAIL1. From a pharmacological point of view, specifically blocking EDA+ fibronectin deposition could be included in studies to reduce the formation of a pro-metastatic environment.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
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| Enthalten in: |
Breast cancer research : BCR - 25(2023), 1 vom: 14. Nov., Seite 143 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Franco-Valls, Héctor [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 17.11.2023 Date Revised 30.01.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1186/s13058-023-01736-y |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM364559705 |
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| 100 | 1 | |a Franco-Valls, Héctor |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Formation of an invasion-permissive matrix requires TGFβ/SNAIL1-regulated alternative splicing of fibronectin |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 17.11.2023 | ||
| 500 | |a Date Revised 30.01.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s). | ||
| 520 | |a BACKGROUND: As in most solid cancers, the emergence of cells with oncogenic mutations in the mammary epithelium alters the tissue homeostasis. Some soluble factors, such as TGFβ, potently modify the behavior of healthy stromal cells. A subpopulation of cancer-associated fibroblasts expressing a TGFβ target, the SNAIL1 transcription factor, display myofibroblastic abilities that rearrange the stromal architecture. Breast tumors with the presence of SNAIL1 in the stromal compartment, and with aligned extracellular fiber, are associated with poor survival prognoses | ||
| 520 | |a METHODS: We used deep RNA sequencing and biochemical techniques to study alternative splicing and human tumor databases to test for associations (correlation t-test) between SNAIL1 and fibronectin isoforms. Three-dimensional extracellular matrices generated from fibroblasts were used to study the mechanical properties and actions of the extracellular matrices on tumor cell and fibroblast behaviors. A metastatic mouse model of breast cancer was used to test the action of fibronectin isoforms on lung metastasis | ||
| 520 | |a RESULTS: In silico studies showed that SNAIL1 correlates with the expression of the extra domain A (EDA)-containing (EDA+) fibronectin in advanced human breast cancer and other types of epithelial cancers. In TGFβ-activated fibroblasts, alternative splicing of fibronectin as well as of 500 other genes was modified by eliminating SNAIL1. Biochemical analyses demonstrated that SNAIL1 favors the inclusion of the EDA exon by modulating the activity of the SRSF1 splicing factor. Similar to Snai1 knockout fibroblasts, EDA- fibronectin fibroblasts produce an extracellular matrix that does not sustain TGFβ-induced fiber organization, rigidity, fibroblast activation, or tumor cell invasion. The presence of EDA+ fibronectin changes the action of metalloproteinases on fibronectin fibers. Critically, in an mouse orthotopic breast cancer model, the absence of the fibronectin EDA domain completely prevents lung metastasis | ||
| 520 | |a CONCLUSIONS: Our results support the requirement of EDA+ fibronectin in the generation of a metastasis permissive stromal architecture in breast cancers and its molecular control by SNAIL1. From a pharmacological point of view, specifically blocking EDA+ fibronectin deposition could be included in studies to reduce the formation of a pro-metastatic environment | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Breast cancer | |
| 650 | 4 | |a EDA+ Fibronectin | |
| 650 | 4 | |a Extracellular matrix | |
| 650 | 4 | |a Matrix architecture | |
| 650 | 4 | |a Matrix rigidity | |
| 650 | 4 | |a Metastasis | |
| 650 | 4 | |a Myofibroblasts | |
| 650 | 4 | |a SNAIL1 | |
| 650 | 4 | |a TGFβ | |
| 650 | 7 | |a Fibronectins |2 NLM | |
| 650 | 7 | |a Protein Isoforms |2 NLM | |
| 650 | 7 | |a Serine-Arginine Splicing Factors |2 NLM | |
| 650 | 7 | |a 170974-22-8 |2 NLM | |
| 650 | 7 | |a SRSF1 protein, human |2 NLM | |
| 650 | 7 | |a Transforming Growth Factor beta |2 NLM | |
| 650 | 7 | |a SNAI1 protein, human |2 NLM | |
| 650 | 7 | |a Snai1 protein, mouse |2 NLM | |
| 650 | 7 | |a TGFB1 protein, human |2 NLM | |
| 650 | 7 | |a Tgfb1 protein, mouse |2 NLM | |
| 700 | 1 | |a Tusquets-Uxó, Elsa |e verfasserin |4 aut | |
| 700 | 1 | |a Sala, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Val, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Peña, Raúl |e verfasserin |4 aut | |
| 700 | 1 | |a Iaconcig, Alessandra |e verfasserin |4 aut | |
| 700 | 1 | |a Villarino, Álvaro |e verfasserin |4 aut | |
| 700 | 1 | |a Jiménez-Arriola, Martín |e verfasserin |4 aut | |
| 700 | 1 | |a Massó, Pere |e verfasserin |4 aut | |
| 700 | 1 | |a Trincado, Juan L |e verfasserin |4 aut | |
| 700 | 1 | |a Eyras, Eduardo |e verfasserin |4 aut | |
| 700 | 1 | |a Muro, Andrés F |e verfasserin |4 aut | |
| 700 | 1 | |a Otero, Jorge |e verfasserin |4 aut | |
| 700 | 1 | |a García de Herreros, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a Baulida, Josep |e verfasserin |4 aut | |
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