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A stromal Integrated Stress Response activates perivascular cancer-associated fibroblasts to drive angiogenesis and tumour progression
dc.creator | Verginadis I.I., Avgousti H., Monslow J., Skoufos G., Chinga F., Kim K., Leli N.M., Karagounis I.V., Bell B.I., Velalopoulou A., Salinas C.S., Wu V.S., Li Y., Ye J., Scott D.A., Osterman A.L., Sengupta A., Weljie A., Huang M., Zhang D., Fan Y., Radaelli E., Tobias J.W., Rambow F., Karras P., Marine J.-C., Xu X., Hatzigeorgiou A.G., Ryeom S., Diehl J.A., Fuchs S.Y., Puré E., Koumenis C. | en |
dc.date.accessioned | 2023-01-31T10:32:06Z | |
dc.date.available | 2023-01-31T10:32:06Z | |
dc.date.issued | 2022 | |
dc.identifier | 10.1038/s41556-022-00918-8 | |
dc.identifier.issn | 14657392 | |
dc.identifier.uri | http://hdl.handle.net/11615/80583 | |
dc.description.abstract | Bidirectional signalling between the tumour and stroma shapes tumour aggressiveness and metastasis. ATF4 is a major effector of the Integrated Stress Response, a homeostatic mechanism that couples cell growth and survival to bioenergetic demands. Using conditional knockout ATF4 mice, we show that global, or fibroblast-specific loss of host ATF4, results in deficient vascularization and a pronounced growth delay of syngeneic melanoma and pancreatic tumours. Single-cell transcriptomics of tumours grown in Atf4Δ/Δ mice uncovered a reduction in activation markers in perivascular cancer-associated fibroblasts (CAFs). Atf4Δ/Δ fibroblasts displayed significant defects in collagen biosynthesis and deposition and a reduced ability to support angiogenesis. Mechanistically, ATF4 regulates the expression of the Col1a1 gene and levels of glycine and proline, the major amino acids of collagen. Analyses of human melanoma and pancreatic tumours revealed a strong correlation between ATF4 and collagen levels. Our findings establish stromal ATF4 as a key driver of CAF functionality, malignant progression and metastasis. © 2022, The Author(s). | en |
dc.language.iso | en | en |
dc.source | Nature Cell Biology | en |
dc.source.uri | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85131294863&doi=10.1038%2fs41556-022-00918-8&partnerID=40&md5=a0b630496b129cd797612eba99f1d5fa | |
dc.subject | activating transcription factor 4 | en |
dc.subject | angiogenic protein | en |
dc.subject | collagen type 1 | en |
dc.subject | glycine | en |
dc.subject | proline | en |
dc.subject | collagen | en |
dc.subject | activating transcription factor 4 gene | en |
dc.subject | adult | en |
dc.subject | animal cell | en |
dc.subject | animal experiment | en |
dc.subject | animal model | en |
dc.subject | animal tissue | en |
dc.subject | Article | en |
dc.subject | cancer associated fibroblast | en |
dc.subject | cell activation | en |
dc.subject | cellular stress response | en |
dc.subject | cohort analysis | en |
dc.subject | collagen synthesis | en |
dc.subject | collagen type I alpha 1 chain gene | en |
dc.subject | controlled study | en |
dc.subject | correlational study | en |
dc.subject | female | en |
dc.subject | gene deletion | en |
dc.subject | gene expression regulation | en |
dc.subject | gene knockout | en |
dc.subject | human | en |
dc.subject | human tissue | en |
dc.subject | knockout mouse | en |
dc.subject | major clinical study | en |
dc.subject | male | en |
dc.subject | melanoma | en |
dc.subject | metastasis | en |
dc.subject | middle aged | en |
dc.subject | mouse | en |
dc.subject | nonhuman | en |
dc.subject | pancreas tumor | en |
dc.subject | perivascular cell | en |
dc.subject | protein analysis | en |
dc.subject | protein expression level | en |
dc.subject | protein synthesis | en |
dc.subject | single cell analysis | en |
dc.subject | stroma cell | en |
dc.subject | transcriptome sequencing | en |
dc.subject | tumor growth | en |
dc.subject | tumor vascularization | en |
dc.subject | tumor-related gene | en |
dc.subject | animal | en |
dc.subject | fibroblast | en |
dc.subject | genetics | en |
dc.subject | melanoma | en |
dc.subject | metabolism | en |
dc.subject | neovascularization (pathology) | en |
dc.subject | pancreas tumor | en |
dc.subject | pathology | en |
dc.subject | Animals | en |
dc.subject | Cancer-Associated Fibroblasts | en |
dc.subject | Collagen | en |
dc.subject | Fibroblasts | en |
dc.subject | Gene Expression Regulation, Neoplastic | en |
dc.subject | Melanoma | en |
dc.subject | Mice | en |
dc.subject | Mice, Knockout | en |
dc.subject | Neovascularization, Pathologic | en |
dc.subject | Pancreatic Neoplasms | en |
dc.subject | Nature Research | en |
dc.title | A stromal Integrated Stress Response activates perivascular cancer-associated fibroblasts to drive angiogenesis and tumour progression | en |
dc.type | journalArticle | en |
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