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Cellular and Molecular

Molecular features and evolutionary trajectory of ASCL1+ and NEUROD1+ SCLC cells

British Journal of Cancer volume 128, pages 748–759 (2023)Cite this article

Subjects

Abstract

Background

Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer without recognised morphologic or genetic heterogeneity. Based on the expression of four transcription factors, ASCL1, NEUROD1, POU2F3, and YAP1, SCLCs are classified into four subtypes. However, biological functions of these different subtypes are largely uncharacterised.

Methods

We studied intratumoural heterogeneity of resected human primary SCLC tissues using single-cell RNA-Seq. In addition, we undertook a series of in vitro and in vivo functional studies to reveal the distinct features of SCLC subtypes.

Results

We identify the coexistence of ASCL1+ and NEUROD1+ SCLC cells within the same human primary SCLC tissue. Compared with ASCL1+ SCLC cells, NEUROD1+ SCLC cells show reduced epithelial features and lack EPCAM expression. Thus, EPCAM can be considered as a cell surface marker to distinguish ASCL1+ SCLC cells from NEUROD1+ SCLC cells. We further demonstrate that NEUROD1+ SCLC cells exhibit higher metastatic capability than ASCL1+ SCLC cells and can be derived from ASCL1+ SCLC cells.

Conclusions

Our studies unveil the biology and evolutionary trajectory of ASCL1+ and NEUROD1+ SCLC cells, shedding light on SCLC tumourigenesis and progression.

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Fig. 1: Single-cell RNA-Seq revealed the intratumoural heterogeneity of SCLC1.
Fig. 2: NEUROD1+ SCLC cells showed reduced epithelial features and lack EPCAM expression.
Fig. 3: Identification of EPCAM as a cell surface marker to distinguish ASCL1+ SCLC cells from NEUROD1+ SCLC cells.
Fig. 4: ASCL1+ cancer cells can transform into NEUROD1+ cancer cells.
Fig. 5: NEUROD1+ cells exhibited higher metastatic capability than ASCL1+ cells both in vivo and in vitro analyses.

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Data availability

The data generated in this study are publicly available in the Gene Expression Omnibus (GEO) database at GSE164145 and GSE164404. The data that supported the findings of this study are available in the Human Tumour Atlas Network (HTAN) database (RU426, RU1066, RU1145 and RU1229A) [12].

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Acknowledgements

We thank National Human Genetic Resources Sharing Service Platform (2005DKA21300), the National Key Research and Development programme of China: The Net construction of human genetic resource Biobank in North China (2016YFC1201703) and Cancer Biobank of Tianjin Medical University Cancer Institute and Hospital for providing paraffin sections of human SCLC samples.

Funding

This work was supported by the National Natural Science Foundation of China (grants 81825017, 81773034 to ZL, 8217113342, 81872350 to ZM, 82273119 to ZZ), the Ministry of Science and Technology of China (grant 2018YFC1313002 to ZL), the Tianjin Municipal Science and Technology Commission (20JCZDJC00110 to ZL), and the Haihe Laboratory of Cell Ecosystem Innovation Fund (HH22KYZX0025 to ZL).

Author information

Author notes

  1. These authors contributed equally: Xuexi Zhang, Hao Wang, Wenxu Liu.

Authors and Affiliations

  1. Department of Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China

    Xuexi Zhang, Hao Wang, Wenxu Liu, Zengtuan Xiao, Zhenfa Zhang & Zhe Liu

  2. Department of Cell Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China

    Zhenyi Ma & Zhe Liu

  3. Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

    Wenchen Gong

  4. Department of Lung Cancer Surgery, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China

    Jun Chen

  5. Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China

    Zhe Liu

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Contributions

ZL, XZ, and ZM designed the study and wrote the paper. XZ, HW, and WL performed experiments and analysed the results. XZ and WL performed bioinformatics. ZX, JC, WG and ZZ provided lung cancer specimens and resources. GW analysed pathological features of SCLCs. All authors reviewed the manuscript.

Corresponding author

Correspondence to Zhe Liu.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The use of all human lung cancer tissues was approved by the Institutional Review Board of Tianjin Medical University. Informed consents were obtained from all patients, and samples were deidentified prior to analysis. All animal procedures were approved by the Animal Care and Use Committee at Tianjin Medical University and confirmed to the legal mandates and national guidelines for the care and maintenance of laboratory animals.

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Zhang, X., Wang, H., Liu, W. et al. Molecular features and evolutionary trajectory of ASCL1+ and NEUROD1+ SCLC cells. Br J Cancer 128, 748–759 (2023). https://doi.org/10.1038/s41416-022-02103-y

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