Differentiation‐related epigenomic changes define clinically distinct keratinocyte cancer subclasses
Abstract Keratinocyte cancers (KC) are the most prevalent malignancies in fair‐skinned populations, posing a significant medical and economic burden to health systems. KC originate in the epidermis and mainly comprise basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). Here, we...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-09-01
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| Series: | Molecular Systems Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/msb.202211073 |
| _version_ | 1797281510955417600 |
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| author | Llorenç Solé‐Boldo Günter Raddatz Julian Gutekunst Oliver Gilliam Felix Bormann Michelle S Liberio Daniel Hasche Wiebke Antonopoulos Jan‐Philipp Mallm Anke S Lonsdorf Manuel Rodríguez‐Paredes Frank Lyko |
| author_facet | Llorenç Solé‐Boldo Günter Raddatz Julian Gutekunst Oliver Gilliam Felix Bormann Michelle S Liberio Daniel Hasche Wiebke Antonopoulos Jan‐Philipp Mallm Anke S Lonsdorf Manuel Rodríguez‐Paredes Frank Lyko |
| author_sort | Llorenç Solé‐Boldo |
| collection | DOAJ |
| description | Abstract Keratinocyte cancers (KC) are the most prevalent malignancies in fair‐skinned populations, posing a significant medical and economic burden to health systems. KC originate in the epidermis and mainly comprise basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). Here, we combined single‐cell multi‐omics, transcriptomics, and methylomics to investigate the epigenomic dynamics during epidermal differentiation. We identified ~3,800 differentially accessible regions between undifferentiated and differentiated keratinocytes, corresponding to regulatory regions associated with key transcription factors. DNA methylation at these regions defined AK/cSCC subtypes with epidermal stem cell‐ or keratinocyte‐like features. Using cell‐type deconvolution tools and integration of bulk and single‐cell methylomes, we demonstrate that these subclasses are consistent with distinct cells‐of‐origin. Further characterization of the phenotypic traits of the subclasses and the study of additional unstratified KC entities uncovered distinct clinical features for the subclasses, linking invasive and metastatic KC cases with undifferentiated cells‐of‐origin. Our study provides a thorough characterization of the epigenomic dynamics underlying human keratinocyte differentiation and uncovers novel links between KC cells‐of‐origin and their prognosis. |
| first_indexed | 2024-03-07T16:57:34Z |
| format | Article |
| id | doaj.art-f1877efb7d4b4f92a9c149e53c79c250 |
| institution | Directory Open Access Journal |
| issn | 1744-4292 |
| language | English |
| last_indexed | 2024-03-07T16:57:34Z |
| publishDate | 2022-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj.art-f1877efb7d4b4f92a9c149e53c79c2502024-03-03T03:40:55ZengSpringer NatureMolecular Systems Biology1744-42922022-09-01189n/an/a10.15252/msb.202211073Differentiation‐related epigenomic changes define clinically distinct keratinocyte cancer subclassesLlorenç Solé‐Boldo0Günter Raddatz1Julian Gutekunst2Oliver Gilliam3Felix Bormann4Michelle S Liberio5Daniel Hasche6Wiebke Antonopoulos7Jan‐Philipp Mallm8Anke S Lonsdorf9Manuel Rodríguez‐Paredes10Frank Lyko11Division of Epigenetics, DKFZ‐ZMBH Alliance German Cancer Research Center Heidelberg GermanyDivision of Epigenetics, DKFZ‐ZMBH Alliance German Cancer Research Center Heidelberg GermanyDivision of Epigenetics, DKFZ‐ZMBH Alliance German Cancer Research Center Heidelberg GermanyDivision of Epigenetics, DKFZ‐ZMBH Alliance German Cancer Research Center Heidelberg GermanyDivision of Epigenetics, DKFZ‐ZMBH Alliance German Cancer Research Center Heidelberg GermanySingle‐cell Open Lab German Cancer Research Center and Bioquant Heidelberg GermanyDivision of Viral Transformation Mechanisms German Cancer Research Center Heidelberg GermanyTissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg GermanySingle‐cell Open Lab German Cancer Research Center and Bioquant Heidelberg GermanyDepartment of Dermatology University Hospital, Ruprecht‐Karls University of Heidelberg Heidelberg GermanyDivision of Epigenetics, DKFZ‐ZMBH Alliance German Cancer Research Center Heidelberg GermanyDivision of Epigenetics, DKFZ‐ZMBH Alliance German Cancer Research Center Heidelberg GermanyAbstract Keratinocyte cancers (KC) are the most prevalent malignancies in fair‐skinned populations, posing a significant medical and economic burden to health systems. KC originate in the epidermis and mainly comprise basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). Here, we combined single‐cell multi‐omics, transcriptomics, and methylomics to investigate the epigenomic dynamics during epidermal differentiation. We identified ~3,800 differentially accessible regions between undifferentiated and differentiated keratinocytes, corresponding to regulatory regions associated with key transcription factors. DNA methylation at these regions defined AK/cSCC subtypes with epidermal stem cell‐ or keratinocyte‐like features. Using cell‐type deconvolution tools and integration of bulk and single‐cell methylomes, we demonstrate that these subclasses are consistent with distinct cells‐of‐origin. Further characterization of the phenotypic traits of the subclasses and the study of additional unstratified KC entities uncovered distinct clinical features for the subclasses, linking invasive and metastatic KC cases with undifferentiated cells‐of‐origin. Our study provides a thorough characterization of the epigenomic dynamics underlying human keratinocyte differentiation and uncovers novel links between KC cells‐of‐origin and their prognosis.https://doi.org/10.15252/msb.202211073cell‐of‐originepigeneticskeratinocyte cancerssingle‐cell |
| spellingShingle | Llorenç Solé‐Boldo Günter Raddatz Julian Gutekunst Oliver Gilliam Felix Bormann Michelle S Liberio Daniel Hasche Wiebke Antonopoulos Jan‐Philipp Mallm Anke S Lonsdorf Manuel Rodríguez‐Paredes Frank Lyko Differentiation‐related epigenomic changes define clinically distinct keratinocyte cancer subclasses Molecular Systems Biology cell‐of‐origin epigenetics keratinocyte cancers single‐cell |
| title | Differentiation‐related epigenomic changes define clinically distinct keratinocyte cancer subclasses |
| title_full | Differentiation‐related epigenomic changes define clinically distinct keratinocyte cancer subclasses |
| title_fullStr | Differentiation‐related epigenomic changes define clinically distinct keratinocyte cancer subclasses |
| title_full_unstemmed | Differentiation‐related epigenomic changes define clinically distinct keratinocyte cancer subclasses |
| title_short | Differentiation‐related epigenomic changes define clinically distinct keratinocyte cancer subclasses |
| title_sort | differentiation related epigenomic changes define clinically distinct keratinocyte cancer subclasses |
| topic | cell‐of‐origin epigenetics keratinocyte cancers single‐cell |
| url | https://doi.org/10.15252/msb.202211073 |
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