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000182688 0247_ $$2ISSN$$a0099-7374
000182688 0247_ $$2ISSN$$a1538-7445
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000182688 041__ $$aEnglish
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000182688 1001_ $$00000-0001-9987-3888$$aHalperin, Coral$$b0
000182688 245__ $$aGlobal DNA Methylation Analysis of Cancer-Associated Fibroblasts Reveals Extensive Epigenetic Rewiring Linked with RUNX1 Upregulation in Breast Cancer Stroma.
000182688 260__ $$aPhiladelphia, Pa.$$bAACR$$c2022
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000182688 520__ $$aCancer cells recruit and rewire normal fibroblasts in their microenvironment to become protumorigenic cancer-associated fibroblasts (CAF). These CAFs are genomically stable, yet their transcriptional programs are distinct from those of their normal counterparts. Transcriptional regulation plays a major role in this reprogramming, but the extent to which epigenetic modifications of DNA also contribute to the rewiring of CAF transcription is not clear. Here we address this question by dissecting the epigenetic landscape of breast CAFs. Applying tagmentation-based whole-genome bisulfite sequencing in a mouse model of breast cancer, we found that fibroblasts undergo massive DNA methylation changes as they transition into CAFs. Transcriptional and epigenetic analyses revealed RUNX1 as a potential mediator of this process and identified a RUNX1-dependent stromal gene signature. Coculture and mouse models showed that both RUNX1 and its stromal signature are induced as normal fibroblasts transition into CAFs. In breast cancer patients, RUNX1 was upregulated in CAFs, and expression of the RUNX1 signature was associated with poor disease outcome, highlighting the relevance of these findings to human disease. This work presents a comprehensive genome-wide map of DNA methylation in CAFs and reveals a previously unknown facet of the dynamic plasticity of the stroma.The first genome-wide map of DNA methylation in breast cancer-associated fibroblasts unravels a previously unknown facet of the dynamic plasticity of the stroma, with far-reaching therapeutic implications.
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000182688 650_7 $$2NLM Chemicals$$aCore Binding Factor Alpha 2 Subunit
000182688 650_7 $$2NLM Chemicals$$aRUNX1 protein, human
000182688 650_7 $$2NLM Chemicals$$aRunx1 protein, mouse
000182688 650_2 $$2MeSH$$aHumans
000182688 650_2 $$2MeSH$$aMice
000182688 650_2 $$2MeSH$$aAnimals
000182688 650_2 $$2MeSH$$aFemale
000182688 650_2 $$2MeSH$$aCancer-Associated Fibroblasts: metabolism
000182688 650_2 $$2MeSH$$aBreast Neoplasms: genetics
000182688 650_2 $$2MeSH$$aBreast Neoplasms: metabolism
000182688 650_2 $$2MeSH$$aDNA Methylation
000182688 650_2 $$2MeSH$$aUp-Regulation
000182688 650_2 $$2MeSH$$aCore Binding Factor Alpha 2 Subunit: genetics
000182688 650_2 $$2MeSH$$aCore Binding Factor Alpha 2 Subunit: metabolism
000182688 650_2 $$2MeSH$$aFibroblasts: metabolism
000182688 650_2 $$2MeSH$$aEpigenesis, Genetic
000182688 650_2 $$2MeSH$$aTumor Microenvironment: genetics
000182688 7001_ $$0P:(DE-He78)198a73f54b40192a2fdc2bf53ba7ca27$$aHey, Joschka$$b1$$eFirst author$$udkfz
000182688 7001_ $$0P:(DE-He78)ff4024f7bc236e7897d9c18ee19c451f$$aWeichenhan, Dieter$$b2$$udkfz
000182688 7001_ $$00000-0002-0331-772X$$aStein, Yaniv$$b3
000182688 7001_ $$00000-0003-4634-3562$$aMayer, Shimrit$$b4
000182688 7001_ $$0P:(DE-He78)ff1677c63392be9b31a1c8d23db7c9dc$$aLutsik, Pavlo$$b5$$udkfz
000182688 7001_ $$0P:(DE-He78)4301875630bc997edf491c694ae1f8a9$$aPlass, Christoph$$b6$$udkfz
000182688 7001_ $$00000-0002-4570-121X$$aScherz-Shouval, Ruth$$b7
000182688 773__ $$0PERI:(DE-600)2036785-5$$a10.1158/0008-5472.CAN-22-0209$$gVol. 82, no. 22, p. 4139 - 4152$$n22$$p4139 - 4152$$tCancer research$$v82$$x0008-5472$$y2022
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