Single-cell sequencing highlights heterogeneity and malignant progression in actinic keratosis and cutaneous squamous cell carcinoma
- First Affiliated Hospital of Kunming Medical University, China
- Sun Yat-sen University, China
- Shanghai Changzheng Hospital, China
- People's Hospital of Chuxiong Yi Autonomous Prefecture, China
- Qujing Affiliated Hospital of Kunming Medical University, China
- First Affiliated Hospital of Dali University, China
- Wenshan Zhuang and Miao Autonomous Prefecture Specialist Hospital of Dermatology, China
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-seq (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 (TFs) 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.
Data availability
The raw data and gene counts table are available from GEO under accession number (GSE193304). All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.
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Funding
Yunnan Science and Technology Leading Talents Project (2017HA010)
- Li He
National Natural Science Foundation of China (82260517)
- Xin Li
Yunnan High-level Talents Scientific Research Project (2023-KHRCBZ-B13)
- Dan-Dan Zou
Yunnan Province Clinical Research Center for Skin Immune Diseases (2019ZF012)
- Li He
Yunnan Province Clinical Center for Skin Immune Diseases (ZX2019-03-02)
- Li He
Shenzhen Science and Technology Program (JCYJ20190807160011600)
- Xin Li
Shenzhen Science and Technology Program (JCYJ20210324124808023)
- Xin Li
China Postdoctoral Science Foundation (2020M683073)
- Ya-Zhou Sun
Guangzhou Science Technology Project (201904010007)
- Xin Li
Guangdong Provincial Key Laboratory of Digestive Cancer Research (2021B1212040006)
- Xin Li
National Natural Science Foundation of China (81872299)
- Xin Li
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). This study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Kunming Medical University (Approval Number (2020)-L-29), and written informed consent was obtained from all patients.
Copyright
© 2023, Zou et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Single-cell sequencing highlights heterogeneity and malignant progression in actinic keratosis and cutaneous squamous cell carcinoma
eLife 12:e85270.
https://doi.org/10.7554/eLife.85270
