Distinct transcriptional programs of SOX2 in different types of small cell lung cancers

Abstract

SOX2 is recognized as an oncogene in human small cell lung cancer (SCLC), which is an aggressive neuroendocrine (NE) tumor. However, the role of SOX2 in SCLC is not completely understood, and strategies to selectively target SOX2 in SCLC cells remain elusive. Here, we show, using next-generation sequencing, that SOX2 expressed in the ASCL1-high SCLC (SCLC-A) subtype cell line is dependent on ASCL1, which is a lineage-specific transcriptional factor, and is involved in NE differentiation and tumorigenesis. ASCL1 recruits SOX2, which promotes INSM1 and WNT11 expression. Immunohistochemical studies revealed that SCLC tissue samples expressed SOX2, ASCL1, and INSM1 in 18 out of the 30 cases (60%). Contrary to the ASCL1–SOX2 signaling axis controlling SCLC biology in the SCLC-A subtype, SOX2 targets distinct genes such as those related to the Hippo pathway in the ASCL1-negative, YAP1-high SCLC (SCLC-Y) subtype. Although SOX2 knockdown experiments suppressed NE differentiation and cell proliferation in the SCLC-A subtype, they did not sufficiently impair the growth of the SCLC-Y subtype cell lines in vitro and ex vivo. The present results support the importance of the ASCL1–SOX2 axis as a main subtype of SCLC, and suggest the therapeutic potential of targeting the ASCL1–SOX2 axis.

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Fig. 1: SOX2 expression and its target genes in the SCLC cell lines.
Fig. 2: SOX2, ASCL1 and INSM1 expression in the ASCL1-induced pulmonary neuroendocrine carcinoma and SCLC cell lines.
Fig. 3: SOX2 knockdown experiments in the SCLC cell lines.
Fig. 4: SOX2 knockdown in the SCLC-Y subtype cell lines, SBC3 and H69AR cells, using RNAi.
Fig. 5: Distinct roles for SOX2 in SCLC-A and SCLC-Y subtypes cells are summarized.

Dataset availability

The dataset produced in this study is available in the following database: SRA accession: PRJNA611338 RNA-seq dataset: Gene Expression Omnibus GSE60052 [22] and the paper-accompanied data are from George et al. (NIHMS782739) [25]. Microarray dataset: GSE62021 [23] and GSE36139 [24].

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Acknowledgements

We thank Ms. Yuko Fukuchi and Ms. Takako Maeda for their technical assistance, the staff of LILA for their technical support, the Institute of Molecular Embryology and Genetics, Kumamoto University, for help with RNA-seq analysis. This study was partially supported by Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (numbers 18K19480 and 20H03691), and by Aihara Pediatric and Allergy Clinic, Yokohama, Japan. This study was also supported in part by the program of the Joint Usage/Research Center for Developmental Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University.

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Correspondence to Takaaki Ito.

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Tenjin, Y., Matsuura, K., Kudoh, S. et al. Distinct transcriptional programs of SOX2 in different types of small cell lung cancers. Lab Invest 100, 1575–1588 (2020). https://doi.org/10.1038/s41374-020-00479-0

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