Single-cell sequencing highlights heterogeneity and malignant progression in actinic keratosis and cutaneous squamous cell carcinoma

eLife · 18 authors, 14 centres

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TL;DR

The study used single-cell RNA sequencing to profile 138,982 cells from human skin samples across the progression from normal skin to actinic keratosis (AK) to cutaneous squamous cell carcinoma (cSCC). It identified malignant basal cell subtypes and key driver genes in early squamous cell carcinoma in situ (SCCIS), suggesting these cells and genes are critical for invasive progression.

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This study employed single-cell RNA sequencing on 13 samples from six human patients, covering normal skin, actinic keratosis (AK), squamous cell carcinoma in situ (SCCIS), and invasive cutaneous squamous cell carcinoma (cSCC), to map the transcriptomic landscape of disease progression. Researchers identified distinct keratinocyte subtypes and discovered that malignant basal cells with specific gene expression profiles emerge in SCCIS, before full invasion. The findings provide a resource for understanding early malignant transformation and potential therapeutic targets in cSCC.

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other

SPECIALTY

dermatology

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ORIGINAL PAPER

PMC10783873

Single-cell sequencing highlights heterogeneity and malignant progression in actinic keratosis and cutaneous squamous cell carcinoma

eLife

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ABSTRACT

Cutaneous squamous cell carcinoma (cSCC) is the second most frequent of the keratinocyte-derived malignancies with actinic keratosis (AK) as a precancerous lesion. To comprehensively delineate the underlying mechanisms for the whole progression from normal skin to AK to invasive cSCC, we performed single-cell RNA sequencing (scRNA-seq) to acquire the transcriptomes of 138,982 cells from 13 samples of six patients including AK, squamous cell carcinoma in situ (SCCIS), cSCC, and their matched normal tissues, covering comprehensive clinical courses of cSCC. We identified diverse cell types, including important subtypes with different gene expression profiles and functions in major keratinocytes. In SCCIS, we discovered the malignant subtypes of basal cells with differential proliferative and migration potential. Differentially expressed genes (DEGs) analysis screened out multiple key driver genes including transcription factors along AK to cSCC progression. Immunohistochemistry (IHC)/immunofluorescence (IF) experiments and single-cell ATAC sequencing (scATAC-seq) data verified the expression changes of these genes. The functional experiments confirmed the important roles of these genes in regulating cell proliferation, apoptosis, migration, and invasion in cSCC tumor. Furthermore, we comprehensively described the tumor microenvironment (TME) landscape and potential keratinocyte-TME crosstalk in cSCC providing theoretical basis for immunotherapy. Together, our findings provide a valuable resource for deciphering the progression from AK to cSCC and identifying potential targets for anticancer treatment of cSCC.

CITATION EXPORT

Dan-Dan Zou, Ya-Zhou Sun, Xin-Jie Li et al.. Single-cell sequencing highlights heterogeneity and malignant progression in actinic keratosis and cutaneous squamous cell carcinoma. eLife. (2023). https://doi.org/10.7554/eLife.85270

AUTHORS

18 · 14 CENTRES

Dan-Dan Zou, Ya-Zhou Sun, Xin-Jie Li, Wen-Juan Wu, Dan Xu, Yu-Tong He, Jue Qi, Ying Tu, Yang Tang, Yun-Hua Tu, Xiao-Li Wang, Xing Li, Feng-Yan Lu, Ling Huang, Heng Long, Li He, Xin Li, Beate Maria Lichtenberger

1 https://ror.org/02g01ht84Department of Dermatology, First Affiliated Hospital of Kunming Medical University Yunnan China
2 https://ror.org/00c099g34Department of Dermatology, The Affiliated Hospital of Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming Yunnan China
3 https://ror.org/00rfd5b88Clinical Big Data Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University Shenzhen, Guangdong China
4 https://ror.org/0064kty71School of Medical, Shenzhen Campus of Sun Yat-sen University Shenzhen, Guangdong China
5 https://ror.org/0103dxn66Department of Dermatology, Changzheng Hospital, Naval Medical University Shanghai China
6 Department of Dermatology, People's Hospital of Chuxiong Yi Autonomous Prefecture, Chuxiong Yunnan China
7 Department of Dermatology, Qujing Affiliated Hospital of Kunming Medical University, The First People’s Hospital of Qujing Yunnan China
8 Department of Dermatology, First Affiliated Hospital of Dali University, Dali Yunnan China
9 Wenshan Zhuang and Miao Autonomous Prefecture Dermatology Clinic, Wenshan Zhuang and Miao Autonomous Prefecture Specialist Hospital of Dermatology, Wenshan Yunnan China
10 https://ror.org/00rfd5b88Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University Guangdong China
https://ror.org/05n3x4p02Medical University of Vienna Austria
https://ror.org/0220mzb33King's College London United Kingdom
https://ror.org/05n3x4p02Medical University of Vienna Austria
https://ror.org/05n3x4p02Medical University of Vienna Austria

EDITOR / REVIEWER

Beate Maria Lichtenberger, Tony Ng, Beate Maria Lichtenberger